Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:36]1([C@@H:42]2[CH2:44][C@H:43]2[C:45](Cl)=[O:46])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[C:24]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)[C:45]([C@@H:43]3[CH2:44][C@H:42]3[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:46])[CH:23]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N1CCc2ccc(N(C(=O)[C@@H]3C[C@H]3c3ccccc3)C3CCN(Cc4ccccc4)CC3)cc21
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (0.353 g, 1.01 mmol) in 50 mL of acetonitrile was added diisopropylethylamine (0.193 mL, 1.11 mmol) and trans-2-phenyl-1-cyclopropanecarbonyl chloride (90%, 0.174 mL, 1.01 mmol). The reaction mixture was stirred overnight, and then was filtered through diatomaceous earth. The filtrate was evaporated and the residue was chromatographed over silica gel (acetone/MeOH/CH2Cl2) to provide the desired product as a tan solid (0.30 g, 61%). 1H NMR (400 MHz, CDCl3): 8.04 (s, 1H), 7.38-6.98 (m, 9H), 6.97-6.82 (m, 2H), 6.76 (dd, J=12.5, 6.2 Hz, 1H), 4.65 (br t, J=12.7 Hz, 1H), 4.12 (t, J=9.5 Hz, 1H), 4.09-3.87 (m, 1H), 3.44 (s, 2H), 3.26-3.07 (m, 2H), 2.97-2.79 (m, 2H), 2.51-2.47 (m, 1H), 2.29-1.98 (m, 5H), 1.92-1.66 (m, 2H), 1.65-1.29 (m, 4H), 1.08-0.96 (m, 1H). MS: exact mass calculated for C32H35N3O2, 493.27; m/z found, 494.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:13]([Cl:12])[CH:14]=2)=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(Br)ccc1O
Reaction time: 18 h
Yield: 46.2 %

Procedure:
A slurry of 5-bromosalicylic acid (15 g, 69 mmol) and 3,4-dichloroaniline (19.85 g, 73 mmol) and phosphorous trichloride (4.74 g 34.5 mmol) in 300 ml of chlorobenzene was refluxed for 3 hr. The hot solution was filtered through a glasswool plug and allowed to stand at room temperature for 18 hr. The crystals which deposited were collected by filtration and washed with fresh chlorobenzene and then methylene chloride to give after drying 19 g (76%) of product mp 230-233°. HPLC tr 19.25 min (Vydac HS5215 C18 ODS, 2.1×150 mm, 0.2 mL/min, gradient, A: water−0.1% trifluoroacetic acid B: acetonitrile−0.1% trifluoroacetic acid, 90-10% A during 20 min, UV detection at 214 nm). Recrystallization from chlorobenzene and then acetone gave 11.5 g of crystals, mp 237-2380°. The structure was verified by X-ray crystallography.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[CH2:14]([C:16]1[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:15]>C(N(CC)CC)C>[CH2:14]([C:16]1[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:26][CH2:25]1)[CH3:15]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CCc1cccc(N2CCNCC2)c1CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1cccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1CC

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with (2,3-diethylphenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(2,3-diethylphenyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+].Cl>C(O)C.O>[CH2:27]([O:26][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]2[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1CCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
The above 5-benzyloxy-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (0.2 g, 0.44 mmol, 1.0 equiv) was dissolved in 5 mL of ethanol. A solution of lithium hydroxide hydrate (0.2 g) in 5 mL of water was added and the resulting solution was stirred for 16 h at ambient temperature. The pH was adjusted to <1 with concentrated HCl and the product was quickly extracted with 2×15 mL of ethyl acetate. The organic layers were combined, dried over Na2SO4, decanted and concentrated to provide 5-benzyloxy-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid (186 mg) as a beige glass.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[N:11][CH:12]=[C:13]([CH:24]=2)[C:14]([NH:16][CH2:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:32][O:33][NH2:34]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:25][CH2:26][C:27]([F:30])([F:28])[F:29])=[N:11][CH:12]=[C:13]([CH:24]=2)[C:14]([NH:16][CH2:17]/[C:18](=[N:34]/[O:33][CH3:32])/[C:19]([F:20])([F:21])[F:22])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(NCC(=O)C(F)(F)F)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CCO
Product: CO/N=C(/CNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1)C(F)(F)F
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of 0.241 g 5-(3,4-dichloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(3,3,3-trifluoro-2-oxo-propyl)-nicotinamide in ethanol was added 0.051 g O-methylhydroxylamine hydrochloride and the mixture was kept at ambient temperature for 18 h. The mixture was then heated to reflux for 4 h. The clear reaction mixture was diluted with ca 2 ml water and concentrated under aspirator vacuum whereby crystallisation occurred. The product was collected by filtration and washed with water and dried to constant weight under high vacuum to yield 0.23 g of the title compound as white crystals melting at 124-126° C. MS (EI): 502.1 (M−H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[N:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[N:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=23)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:21]([O:25][C:26](=[O:27])[NH:28][C@H:29]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:30][C:31]([N:14]1[CH2:15][CH2:16][N:11]2[C:10]([C:17]([F:18])([F:20])[F:19])=[N:9][C:8]([C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])=[C:12]2[CH2:13]1)=[O:32])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: O=C(c1nc(C(F)(F)F)n2c1CNCC2)C1CCCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)C3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 70.8 %

Procedure:
Cyclopentyl-(3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl)-methanone 28b (83 mg, 0.258 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (0.129 g, 0.388 mmol) were dissolved in 10 mL of dichloromethane under stirring, and triethylamine (0.143 mL, 1.03 mmol) was then added to the solution. After stirring to mix well, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.099 g, 0.388 mmol) was added. The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-cyclopentanecarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 28c (0.11 g, yield 72%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[C:14](=[O:16])[N:13]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:25]([O:33]C([O-])=O)([O:27][CH:28]([CH2:30][CH2:31][CH3:32])[CH3:29])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:29][CH:28]([O:27][C:25]([N:13]1[C:12]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:11]2[C:15](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]([C:25]([O:27][CH:28]([CH2:30][CH2:31][CH3:32])[CH3:29])=[O:33])[C:10]2=[O:24])[C:14]1=[O:16])=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: O=c1nc(-c2ccc(Cl)cc2)c2c(=O)nc(-c3ccc(Cl)cc3)c1=2
Reactant: CCCC(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCC(C)OC(=O)N1C(=O)C2=C(c3ccc(Cl)cc3)N(C(=O)OC(C)CCC)C(=O)C2=C1c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
4.28 g of 3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione, 5.91 g 2-pentyl dicarbonate from Example B2, 0.40 g of 4-dimethylaminopyridine and 500 ml of dry tetrahydrofuran are mixed and the mixture is stirred at 55° C. for 4 hours. The suspension is filtered off with suction on a glass microfilter supporting a cotton filter, the solvent is evaporated off under reduced pressure, and the residue is admixed with 50 ml of isopropanol. After 30 minutes the precipitate is filtered off with suction and washed with 15 ml of isopropanol, and the yellow product is dried under reduced pressure to leave 2.86 g (41% of theory) of 2,5-di-2-pentyloxycarbonyl-3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione as yellow powder. NMR (CDCl3) [ppm]: 67 =7.65 ppm (d,4H), 7.46 (d,4H), 4.98 (m,2H), 1.67-1.35 (m,8H), 1.26 (d,6H), 0.88 (t,6H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[C:6]1(=[O:12])C[CH2:10][CH2:9][CH2:8][CH2:7]1.C(OCC)=O>CCOCC>[OH:5][CH:3]=[C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:12]
Reactant: O=C1CCCCC1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC=O
Product: O=C1CCCCC1=CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 50% sodium hydride dispersion in oil (24 g., 0.5 mole) and absolute ethanol (2.5 ml., 43 mmole) in 1 liter ether were stirred under N2 at 0° C. To the cold solution, cyclohexanone (51.5 ml., 0.5 mole) in ethyl formate (60 ml., 0.75 mole) was added dropwise at 0°-5° C. The cooling bath was removed. The temperature rose to the boiling point of ether over 30 minutes. The reaction mixture was recooled, warmed gradually to room temperature over 6 hours and finally stirred for an additional 16 hours. Ether lost by evaporation was replaced by diluting to 1 liter with fresh ether. Ethanol (12.5 ml.) was added and stirring continued for 1 hour. The mixture was extracted with 125 ml. water in two portions. The combined aqueous extracts were washed 1×50 ml. ether, acidified with 82 ml. 6N HCl, and extracted 2×150 ml. with fresh ether. The acid ether extracts were combined, washed 1×25 ml. brine, dried over Na2SO4, evaporated to an oil and distilled to yield title product, 44 g., b.p. 92°-98°/15-20 mm.
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)=[N+:2]=[N-:3].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl.N1C=CC=CC=1>[N:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][C:16](=[O:18])[CH3:17])[CH:8]=2)=[N+:2]=[N-:3]
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=Nc1cc2ccc(O)cc2oc1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2cc(N=[N+]=[N-])c(=O)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a stirred suspension of 3-azido-7-hydroxycoumarin (203 mg, 1.0 mmol) in dry CH2Cl2 (15 mL), acetic anhydride (1.5 mmol) and pyridine (one drop) were added. Upon stirring overnight at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with H2O. The organic layer was dried over anhydrous Na2SO4 and concentrated. Purification with column chromatography over silica gel (hexane-EtOAc 4:1) afforded the final product as a yellow solid (210 mg, 86%). 1H-NMR (DMSO-d6, 300 MHz) δ 2.29 (s, 3H), 7.17 (dd, J=8.0, 2.0 Hz, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.67 (s, 1H), 7.70 (d, J=7.9 Hz, 1H). 13C NMR (DMSO-d6, 75 MHz) δ 21.5, 110.6, 117.8, 119.9, 125.8, 126.8, 129.2, 151.9, 152.3, 157.5, 169.6. IR (KBr): 2133 (vs), 1749, 1730 (vs), 1622 (s), 1234 (s). EI-HRMS m/e calculated for M+ C11H7N3O4 245.0437; found 245.0432.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.CN(C)CCN(C)C.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C.Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[B:28]([OH:29])[OH:27]
Reactant: COc1cccc(OC)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cccc(OC)c1B(O)O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 1,3-dimethoxybenzene (33.2 g, 240 mmol) in hexanes (20 mL) at −20° C. was treated sequentially with n-butyllithium (100 mL of a 2.4M solution in hexanes, 240 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.81 mL, 12 mmol), stirred for 1.5 hours, cooled to −78° C., treated with triisopropylborate (60.9 mL, 264 mmol) in diethyl ether (60 mL) over 1.5 hours with additional diethyl ether (150 mL) added to maintain stirring, stirred at 23° C. for 2 hours, poured into ice (150 mL) and 3M HCl (150 mL), and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated, during which a white solid precipitated. The solid was collected by filtration and washed with hexanes to provide the desired compound, which used without further purification. MS (DCI/NH3) m/z 200 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:17].O>O1CCCC1>[CH3:17][O:15][C@H:12]1[CH2:13][CH2:14][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
Sodium hydride (2.2 g, 80% dispersion in mineral oil, 73.2 mmol) was added to an ice-cooled solution of (3S)-N-tert-butoxycarbonylpyrrolidin-3-ol (U.S. Pat. No. 6,180,627 preparation 78), (12.5 g, 66.7 mmol) in tetrahydrofuran (330 ml), and the solution was stirred at room temperature for an hour. Iodomethane (14.5 g, 100 mmol) was then added and the reaction stirred for 18 hours. Water (100 ml) was added and the mixture concentrated under reduced pressure to remove the organic solvents. The solution was partitioned between water (750 ml) and ethyl acetate (750 ml) the layers separated, and the organic solution dried over magnesium sulphate and evaporated under reduced pressure to give the title compound.
Reaction SMILES: CCOC1C=CC(N)=CC=1.Cl[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17](Cl)[C:13]=1[C:14]([OH:16])=[O:15].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[N+:21]([C:20]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])([O-:23])=[O:22]
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: CCOc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: O=C(O)c1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 28.0 g (0.20 mol) of p-phenetidine, 23.6 g (0.10 mol) of 2,6-dichloro-3-nitrobenzoic acid, and 80 ml of N,N-dimethylaniline was heated five hours on a steam bath. The resulting mixture was diluted with chloroform and extracted with 1N aq. NaOH. Acidification of the aqueous extract yielded 6-chloro-2-[4-ethoxyphenyl)amino]-3-nitrobenzoic acid as reddish brown crystals, mp 174°-176° C.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH:9]1([NH:12][C:2]2[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=2)[CH2:11][CH2:10]1
Reactant: NC1CC1
Reactant: Clc1ncncc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Ic1cncnc1NC1CC1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
To a vial containing a solution of 4-chloro-5-iodopyrimidine (0.400 g, 1.664 mmol) in DMF (Volume: 2.67 ml) was added cyclopropanamine (0.461 ml, 6.65 mmol) followed by cesium carbonate (1.084 g, 3.33 mmol). The vial was sealed with a Teflon cap and heated at 90° C. for 3 h, then allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with EtOAc. The filtrate was diluted with H2O and the layers were separated. The organic phase was washed with H2O (2×). The combined aqueous phases were back-extracted with EtOAc (3×). All organics were combined, dried over Na2SO4, filtered, and concentrated to afford an orange residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 20-70% EtOAc in hexanes over 19 min, ret. T=13.5 min) gave Intermediate 108A (348 mg, 1.320 mmol, 79% yield) as a yellow solid. MS (ESI): m/z=262.0 [M+H]+ HPLC Peak ret. T=1.47 minutes was product. (HPLC conditions: Column:Luna C18 4.6×30 mm 3 u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].C[Al](C)C.CO[C:13]([C:15]1[CH:16]=[N:17][C:18]([C:21]2([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1)=[O:14]>ClCCCl.C(Cl)Cl>[CH2:2]([N:4]([CH2:5][CH3:6])[C:13]([C:15]1[CH:16]=[N:17][C:18]([C:21]2([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[N:19][CH:20]=1)=[O:14])[CH3:3]
Reactant: CCNCC
Reactant: COC(=O)c1cnc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cnc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a stirring suspension of diethyl amine hydrochloride (986 mg, 9.01 mmol) in 1,2-dicloroethane (25 mL) at 0° C. was added a 2.0 M solution of AlMe3 (4.5 mL, 9.01 mmol) dropwise. The resulting mixture stirred at room temperature for 1 hour. (2-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid methyl ester (750 mg, 1.80 mmol) was added in one portion and the mixture was heated to 85° C. for 16 hours. The reaction was slowly poured into a saturated solution of Rochelle salts (50 mL) and diluted with CH2Cl2 (50 mL). The layers were separated, the aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were dried and concentrated. The crude material was filtered through a plug of silica gel with 5% MeOH/CHCl3, and the resulting solution was concentrated to yield 815 mg (99% yield) of the desired amide. 1HNMR (400 MHz, CDCl3) δ 8.72 (s, 2H), 7.29-7.14 (comp, 6H), 6.97-6.95 (comp, 2H), 6.68-6.66 (comp, 1H), 3.73 (s, 3H), 3.54-3.52 (comp, 2H), 3.39 (s, 2H), 3.27-3.25 (comp, 2H), 2.98-2.95 (comp, 2H), 2.77-2.74 (comp, 2H), 2.34-2.31 (comp, 2H), 2.16-2.02 (comp, 2H), 1.26-1.17 (comp, 6H); MS (M+1) 459.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[CH:21]=[CH2:22].I[CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C>[CH2:24]([O:19][C:18]([C:4]1[C:3]([CH:21]=[CH2:22])=[C:2]([NH2:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=1)=[O:20])[CH2:25][CH2:26][CH3:27]
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OCCCC
Temperature: 60 °C
Yield: 52.7 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylic acid (0.150 g, 0.46 mmol), iodobutane (0.111 g, 0.60 mmol), and lithium carbonate (0.044 g, 0.6 mmol) were combined in DMF (1.5 mL) and heated at 60° C. overnight. The cooled reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic phase was dried and concentrated. The product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (0.092 g, 52.3% yield): 1H NMR (CDCl3) δ 7.65 (dd, 1H), 7.19 (dd, 1H), 7.75 (dd, 1H), 5.62-5.67 (m, 2H), 5.35 (br s, 2H), 4.34 (t, 3H), 3.99 (dd, 3H), 1.74 (m, 2H), 1.45 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32]>>[CH3:32][C:31]([OH:33])([CH3:34])[CH2:30][NH:29][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[N:7]=1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(O)CN
Product: Cn1cc(-c2cc3c(-c4cccc(NCC(C)(C)O)n4)n[nH]c3cn2)cn1
Yield: 87 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 1-amino-2-methyl-propan-2-ol were reacted. The product was deprotected and purified to give 297 as a white solid (87% over two steps). 1H NMR (400 MHz, DMSO) δ 13.62 (broad s, 1H), 9.01 (s, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.3 Hz, 1H), 6.63-6.56 (m, 2H), 4.73 (s, 1H), 3.89 (s, 3H), 3.56 (d, J=5.8 Hz, 2H), 1.25 (s, 6H). LC/MS: m/z 364.2 [M+1]
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[CH:19][C:20]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:21]([CH:31]=1)[C:22]([NH:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:23]>COCCOC.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>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][O:32][C:20]2[CH:19]=[CH:18][C:17]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])=[CH:35][CH:36]=1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reactant: Cn1nccc1B(O)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: COCCOC
Product: Cn1nccc1-c1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Temperature: 120 °C

Procedure:
(1-Methyl-1H-pyrazol-5-yl)boronic acid (30.1 mg, 0.24 mmol), sodium carbonate (0.40 ml, 0.40 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.82 mg, 0.01 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared as described in Example 59; 80 mg, 0.20 mmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated at 120° C. for 1 hour. The solvent was removed in vacuo and purified by MDAP to yield the title compound as a brown gum. 13 mg.