Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I:28][C:29]1[CH:30]=[CH:31][C:32]([S:35](Cl)(=[O:37])=[O:36])=[N:33][CH:34]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:35]([C:32]1[CH:31]=[CH:30][C:29]([I:28])=[CH:34][N:33]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(I)cn1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(I)cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,4-Dimethoxy-benzyl)-thiazol-2-yl-amine (0.453 g, 1.81 mmol) was dissolved in Tetrahydrofuran (5 mL, 70 mmol) and cooled in an ice bath. 1.0 M of Lithium hexamethyldisilazide in Tetrahydrofuran (2.0 mL) was added dropwise to the reaction. After addition was complete, the reaction mixture was warmed to ambient temperature. After 30 min, the reaction was cooled to at 0° C. and a solution of 5-Iodo-pyridine-2-sulfonyl chloride (0.50 g, 1.6 mmol) in Tetrahydrofuran (4 mL, 50 mmol) was added dropwise. The reaction mixture was stirred 4 h then quenched with saturated aqueous ammonium chloride. The reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and additional saturated aqueous ammonium chloride was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered through celite, and concentrated in vacuo. The residue was purified on the ISCO twice (hexanes to ethyl acetate) to afford the product as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[N:30](COCC[Si](C)(C)C)[C:29](=[O:39])[O:28][CH2:27][C:26]=3[CH:40]=2)[CH2:18][CH2:17]1.Cl.O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[NH:30][C:29](=[O:39])[O:28][CH2:27][C:26]=3[CH:40]=2)[CH2:18][CH2:17]1
Reactant: Cn1c(OC2CCN(c3ccc4c(c3)COC(=O)N4COCC[Si](C)(C)C)CC2)nc(-c2ccncn2)cc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(OC2CCN(c3ccc4c(c3)COC(=O)N4)CC2)nc(-c2ccncn2)cc1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 36.4 %

Procedure:
To a solution of 1-methyl-2-{[1-(2-oxo-1{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-2H-3,1-benzoxazin-6-yl)piperidin-4-yl]oxy}-1H-[4,4′]bipyrimidinyl-6-one (78 mg, 0.14 mmol) in tetrahydrofuran (1.4 ml) was added 6N aqueous hydrochloric acid (1.4 ml, 8.4 mmol). The mixture was stirred at 70° C. for 3 hours. The mixture was poured into water. The aqueous solution was neutralized with sodium hydrogen carbonate. Extraction with dichloromethane was performed three times. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; chloroform/methanol=98/2) to afford 1-methyl-2-{[1-(2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)piperidin-4-yl]oxy}-1H-[4,4′]bipyrimidinyl-6-one as a pale yellow solid (22 mg, 0.051 mmol, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:24])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:25](N)(C)C.[Li].[N+](=C)=[N-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:24])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[C@H:11]([CH3:25])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: COc1ccc(CN2C(=O)COC[C@@]2(C)c2cccc(Br)c2)cc1
Agent: C=[N+]=[N-]
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@H](C)OC[C@@]2(C)c2cccc(Br)c2)cc1
Temperature: -75 °C

Procedure:
A dried flask was charged under an argon atmosphere with a solution of (R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-5-methyl-morpholin-3-one (600 mg, 1.5 mmol) in tetrahydrofuran (16 ml) which was cooled to −75° C. Lithium isopropylamine (1.54 ml, 3 mmol) was added, and after the addition of diazomethane (502 mg, 3.5 mmol) the reaction was complete. For the workup, the cold reaction mixture was quenched with a saturated ammonium chloride solution (15 ml) and extracted with a mixture of dichloromethane (40 ml) and water (15 ml). The organic layer was dried over sodium sulfate and evaporated to yield the crude (2S,5R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,5-dimethyl-morpholin-3-one as a brownish oil which was engaged in the next step without further purification. Mass (calculated) C20H22BrNO3 [404.307]; (found) [M+H]+=404, [M+2-H]+=406.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:16][C:17]([CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH:73]1[CH2:77][CH2:76][CH2:75][CH2:74]1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:21][C:17]1[CH:16]=[C:15]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([N:73]4[CH2:77][CH2:76][CH2:75][CH2:74]4)=[CH:4][CH:5]=3)=[CH:12][CH:13]=2)[N:18]=1
Reactant: C1CCNC1
Reactant: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(Cl)nc3)cc2n1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(N4CCCC4)nc3)cc2n1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A suspension of 98.5 mg (0.25 mmol) of 7-(6-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride, product of example 56, 16 mg (0.03 mmol) of BINAP, 2.8 mg (0.01 mmol) of Pd(II) acetate, and 99 mg (1 mmol) of sodium tert-butylate in toluene (4.5 ml) was treated at RT with 36 mg (0.5 mmol) of pyrrolidine and then heated at reflux under an argon atmosphere for 4 h. The reaction mixture was cooled to RT, diluted with methylene chloride (10 ml), and then filtered. The filtrate was concentrated in vacuo, the residue triturated with ether, filtered off by suction and dried in a high vacuum to give 88 mg (84%) of the 2-methyl-4-pyrrolidin-1-yl-7-(6-pyrrolidin-1-yl-pyridin-3-ylmethoxy)-quinoline as a white solid. ISP mass spectrum, m/e: 389.3 (M+1 calculated for C24H28N4O: 389).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26](Br)[CH:27]=[CH2:28]>C1(C)C=CC=CC=1>[CH2:28]([N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: c1ccc(Oc2ccc(C3CCCN3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCN1CCCC1c1ccc(Oc2ccccc2)cc1

Procedure:
8 parts of 2-(4-phenoxyphenyl) pyrrolidine, 3.3 parts of triethylamine, 4 parts of allyl bromide and 70 parts of toluene were refluxed for 5 hours. After cooling and filtration, there were obtained by distillation 7.7 parts of 1-allyl-2-(4-phenoxyphenyl) pyrrolidine, B.P./0.2 mm Hg: 148°-150° C., nD26 =1.5695, M.P. of its acid fumarate: 115°-116° C. (isopropanol/ether).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]4)[N:12]=3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:28].[C:29](#[N:32])[CH:30]=[CH2:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:28][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1/[CH:31]=[CH:30]/[C:29]#[N:32])[NH:8][CH:7]=[C:6]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1
Reactant: C=CC#N
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(Cl)c(F)cc34)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(/C=C/C#N)c(F)cc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 253 and acrylonitrile, followed by TBAF deprotection of the SEM group.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23]Br)[CH:7]=1)[CH3:2].[F:26][C:27]([F:31])([F:30])[CH2:28][SH:29]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][S:29][CH2:28][C:27]([F:31])([F:30])[F:26])[CH:7]=1)[CH3:2]
Reactant: FC(F)(F)CS
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1

Procedure:
As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]acetic acid ethyl ester and 2,2,2-trifluoroethanethiol were reacted to provide {4-chloro-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester, which was reduced to the amine and then treated with pivaloyl chloride to provide {4-chloro-3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=O)[CH2:19]Br)=[C:13]([CH3:22])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:23][C:24]([NH2:26])=[S:25]>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18]4[N:23]=[C:24]([NH2:26])[S:25][CH:19]=4)=[C:13]([CH3:22])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cc(Oc2ccc3c(c2)OCO3)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(Oc2ccc3c(c2)OCO3)cc(C)c1-c1csc(N)n1
Yield: 95.6 %

Procedure:
A mixture of 1-(4-(benzo[d][1,3]dioxol-5-yloxy)-2,6-dimethylphenyl)-2-bromoethanone (6.13 g, 16.9 mmol) and thiourea (1.29 g, 16.9 mmol) in 95% EtOH (24.1 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(benzo[d][1,3]dioxol-5-yloxy)-2,6-dimethylphenyl)thiazol-2-amine (5.50 g) as yellow solids in 96% yield: 1H NMR (500 MHz, CDCl3) δ 6.75 (d, J=8.5 Hz, 1H), 6.66 (s, 2H), 6.58 (m, 1H), 6.49 (m, 1H), 6.28 (s, 1H), 5.98 (s, 2H), 5.05 (bs, 2H), 2.13 (s, 6H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)[CH3:3].CCN(C(C)C)C(C)C.O=C1CCC(=O)N1[O:42][C:43](=O)[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Br:52]>C(Cl)Cl>[Br:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[CH2:45][O:44][C:43]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]1[C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:25])=[O:42]
Reactant: O=C(OCc1ccccc1Br)ON1C(=O)CCC1=O
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (836 mg, 2.00 mmol, 1.0 eq.) and DIPEA (0.86 mL, 5.00 mmol, 2.5 eq.) in DCM (30 mL), carbonic acid 2-bromo-benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (787 mg, 2.40 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. during 2 hours. The reaction was quenched with 1M aq. citric acid soln. (30 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. To a solution of the previous mixture in EtOH (1.1 mL), conc. H2SO4 (0.10 mL) was added. The solution was stirred at r.t. during 3 hours. Water and 5% aq. NaOH soln. were added and the mixture was extracted with DCM (3×). The comb. org. phases were dried over MgSO4, filtered and concentrated in vacuo to give the desired product as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH2:17]([S:20]Cl)[CH2:18][CH3:19].C(SSCCC)CC.ClCl>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:20][CH2:17][CH2:18][CH3:19])=[C:7]([OH:11])[CH:6]=1
Reactant: Oc1cccc(Oc2ccc(Cl)cc2Cl)c1
Reactant: CCCSCl
Agent: CCCSSCCC
Agent: ClCl
Solvent: ClCCl
Product: CCCSc1ccc(Oc2ccc(Cl)cc2Cl)cc1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3-(2,4-Dichlorophenoxy)phenol (0.1 mole) and methylene chloride (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. The mixture is stirred until dissolved and cooled to about -20° C. A solution of propyl sulfenyl chloride freshly prepared by reacting dipropyl disulfide (0.15 mole) with chlorine (0.18 mole) in methylene chloride (100 ml) is then added dropwise to the reaction vessel over a period of about 40 minutes. After the addition is completed stirring is continued for 30 minutes with cooling and 30 minutes at room temperature. After this time the reaction mixture is washed with water (200 ml), with 5% aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The washed solution is then dried by passing it through a phase separator. The dried solution is stripped of solvent under reduced pressure and the residue chromatographed using a clay column and hexane/ethyl acetate as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product 5-(2,4-dichlorophenoxy) 2-(propylthio)phenol as the residue.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[N:19]([Sn](C)(C)C)[N:18]=[N:17][N:16]=3)[CH:11]=[CH:10][C:9]=2[NH2:24])=[CH:4][CH2:3]1.[K+].[C:27]([C:29]1[N:30]=[C:31]([C:42]([O-])=[O:43])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=1)#[N:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:11]=[CH:10][C:9]=2[NH:24][C:42]([C:31]2[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[C:29]([C:27]#[N:28])[N:30]=2)=[O:43])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(Cc3nnnn3[Sn](C)(C)C)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(Cc3nnn[nH]3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-trimethylstannanyl-1H-tetrazol-5-ylmethyl)-phenylamine (as prepared in the previous step, 280 mg, 0.626 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 267 mg, 1.56 mmol), PyBroP (466 mg, 1.00 mmol) and DIEA (273 μL, 1.56 mmol) according to the procedure in Example 11, step (f) (128 mg, 38%). 1H-NMR (CDCl3; 400 MHz): δ9.72 (s, 1H), 8.27 (d, 1H, J=8.3 Hz), 7.76 (s, 1H), 7.19 (m, 1H), 7.12 (s, 1H), 5.94 (s, 2H), 5.70 (s, 1H), 4.29 (s, 2H), 3.66-3.64 (m, 2H), 2.27-2.25 (m, 2H), 2.07-2.06 (m, 2H), 1.56-1.51 (m, 2H), 1.09 (s, 6H), 0.99-0.94 (m, 2H), 0.01 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7](OC)[CH:6]=[CH:5]2.C[N:18](C)C=O.N.O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([NH2:18])[CH:6]=[CH:5]2
Reactant: CN(C)C=O
Reactant: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Agent: N
Solvent: O
Solvent: CO
Product: Nc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
6-bromo-2-methoxy-1-nitronaphthalene (12.6 g, 44.7 mmol), dimethylformamide (25.6 mL) and 7N NH3 solution in MeOH (128 mL, purchased from Sigma Aldrich) were combined in a Parr bomb. The bomb was heated in a lab oven at 130° C. After 48 hours, the reactor was removed from the oven and cooled to room temperature. The contents of the bomb were transferred to a glass round bottom flask. The bomb was thoroughly rinsed with dichloromethane and methanol, and the rinsings added to the flask. The contents of the flask were thoroughly concentrated on a rotary evaporator, leaving a brown solid. Water (200 mL) was added to the flask and the resulting suspension was agitated with a stir bar for 30 minutes. The resulting light brown powder was isolated by filtration, rinsing a few times with water. The filter cake was air dried over night to yield 6-bromo-1-nitronaphthalen-2-amine (11.6 g, >95% yield).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F-:15].[K+].CN(C)C=O>O>[F:15][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [F-]
Reactant: CCOC(=O)C(Br)c1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 25.8 %

Procedure:
A mixture of ethyl α-bromo-4-chlorophenylacetate (37.3 g), anhydrous potassium fluoride (9.7 g) and dry dimethylformamide (75 ml) was heated with stirring at a temperature of 140°-150° C. for a period of 6 hours. The reaction mixture was poured into water and the aqueous mixture extracted with methylene dichloride. The organic extract was washed with aqueous sodium carbonate, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The product was distilled using a spinning band column to give ethyl α-fluoro-4-chlorophenylacetate (7.5 g; 29%) b.p. 67° C. at 0.06 mm Hg.
Reaction SMILES: [C:1]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[N:13]=[CH:12][C:11]=2[C:10](I)=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.CO.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>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:10]1[C:11]2[CH:12]=[N:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:15][C:16]=2[N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[N:9]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cnc(Oc3ccc(F)cc3F)cc21
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: c1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2Cl)c2cnc(Oc3ccc(F)cc3F)cc21
Yield: 66 %

Procedure:
A solution of 1-BOC-6-(2,4-difluorophenoxy)-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.071 g) and 2-chlorophenylboronic acid in 5 mL of benzene and 1 mL of methanol was stirred at room temperature for 15 minutes. To this solution was added tetrakis(triphenylphosphine)palladium catalyst (52 mg) and 0.3 mL of 1 M sodium carbonate. The resulting mixture was heated to reflux for five hours, cooled, filtered and the organic layer was separated. The organic layer was washed, dried and concentrated. The residue was purified via chromatography using 5% ethyl acetate in hexane as the eluent to afford 45 mg of 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-pyrazolo[4,3-c]pyridine-1-carboxylic acid, tert-butyl ester (66% yield). Mass. Spec. M+H=458.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[NH:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH2:9][CH2:10][C:11]([O:13][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To mixture of Boc-β-alanine (N-Boc-β-Ala-OH; 1 g, 5.29 mmol) and N-hydroxysuccinimide (0.9 g, 7.82 mmol) in DMF (10 mL) were added 1-hydroxybenzotriazole hydrate (HOBt.xH2O; 0.7 g, 5.25 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl; 1 g, 5.23 mmol) at 5° C. The reaction mixture was warmed to RT and stirred for 16 h. The progress of the reaction was monitored by TLC. The reaction was quenched with water and the mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (3×100 mL) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was triturated with ether (2×25 mL) to afford N-Boc-β-Ala-OSu (1.1 g, crude) as a white solid. 1H NMR (500 MHz, CDCl3): δ 5.10 (br s, 1H), 3.52 (q, J=6.0 Hz, 2H), 2.85-2.82 (m, 6H), 1.31 (s, 9H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]([CH3:59])[C:48]([NH:50][C@@H:51]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:52](=[O:53])[C@H:51]([C:55]([CH3:57])([CH3:56])[CH3:58])[NH:50][C:48](=[O:49])[N:47]([CH3:59])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CN(Cc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1ccccc1)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.4 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 63C (0.013 g, 0.047 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol) and the mixture was stirred at 25° C. for 45 minutes. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.017 g, 57% yield). 1H NMR (300 MHz, DMSO-d) δ ppm 0.80(s, 9H), 0.81(s, 9H), 1.58-1.49(m, 2H), 2.74-2.72(m, 3H), 2.79(s, 3H), 3.49(s, 3H), 3.67-3.61(m, 1H), 3.84-3.81(d, J=9.93 Hz, 1H), 4.12-3.99(m, 1H), 4.16-4.13(d, J=8.82 Hz, 2H), 4.44(s, 2H), 4.82-4.80(d, J=5.88 Hz, 1H), 5.40-5.37(d, J=9.19 Hz, 1H), 6.62-6.59(d, J=9.93 Hz, 1H), 7.35-7.10(m, 13H), 7.67-7.64(d, J=8.82 Hz, 1H), 7.82-7.77(m, 1H), 7.88-7.84(m, 4H), 8.63 (d, J=4.41 Hz, 1 H).