Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18](O)=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:43][C:44]([C:47]([O:49][CH3:50])=[O:48])([CH3:46])[CH3:45].Cl.CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([NH:43][C:44]([C:47]([O:49][CH3:50])=[O:48])([CH3:46])[CH3:45])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: COC(=O)C(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.4 %

Procedure:
A solution containing about 1.5 g of Boc-Tyr(OBn)-OH (5) in 10 ml of dry CH2Cl2 was treated at 0° C. with about 417 mg of DCC. The mixture was stirred at 0° C. for about 5 minutes and treated with a solution containing about 620 mg of Aib-OMe hydrochloride (6) and about 490 mg of NMM in 2 ml of dry DMF. After stirring at 22° C. for about 12 hours, the reaction mixture was extracted with a saturated aqueous solution of NH4Cl. The organic layer was dried over Na2SO4, evaporated to dryness, and the residue chromatographed on SiO2 (EtOAc/hexanes 3:7) to yield about 900 mg of compound 7.
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([O:10][CH3:11])[CH2:6]1.O([Si](C)(C)C)[K].Cl.Cl.Cl.[S:22]1[C:26]2=[C:27]([N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([NH2:45])[CH2:41][CH2:40]4)[CH2:33][CH2:32]3)[N:28]=[CH:29][CH:30]=[C:25]2[CH:24]=[CH:23]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][O:10][C@H:7]1[CH2:8][CH2:9][C@H:5]([CH2:4][C:3]([NH:45][C@H:42]2[CH2:43][CH2:44][C@H:39]([CH2:38][CH2:37][N:34]3[CH2:35][CH2:36][N:31]([C:27]4[N:28]=[CH:29][CH:30]=[C:25]5[CH:24]=[CH:23][S:22][C:26]=45)[CH2:32][CH2:33]3)[CH2:40][CH2:41]2)=[O:12])[CH2:6]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccsc34)CC2)CC1
Reactant: COC(=O)C[C@H]1CC[C@H](OC)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[Si](C)(C)O[K]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CC[C@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5ccsc45)CC3)CC2)C1
Temperature: 25 °C

Procedure:
A mixture of racemic trans-(3-methoxy-cyclopentyl)-acetic acid methyl ester [WO 2009/019174] (41 mg, 0.24 mmol) and KOSiMe3 (51 mg, 0.40 mmol) in CH2Cl2 (1 ml) was stirred at room temperature over night. The solvent was evaporated and DMF (1 ml) was added followed by trans-4-[2-(4-thieno[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A; 90 mg, 0.20 mmol), DIPEA (103 mg, 0.80 mmol) and TBTU (83 mg, 0.26 mmol). After stirring 3 h at room temperature, sat. aq. NaHCO3 sol. was added and the product was extracted with CH2Cl2. The organic layer was dried (MgSO4), the solvent was evaporated and the crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH 95:5) to yield the title compound as a light red foam (65 mg, 68%), MS (ISP) m/z=485.4 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([C:17]2[CH:18]=[CH:19][C:20]3[C:21]4[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]=4[N:23]([CH3:26])[C:24]=3[CH:25]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Product: Cn1c2c(c3ccc(-n4ncc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 43.6 %

Procedure:
5-(Benzyloxy)pyridazin-3(2H)-one (100 mg, 0.5 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (180 mg, 0.5 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (106 mg, 43%) as a solid: ESI MS m/z 487 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1-fluoro-4-isocyanatobenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.45 (q, 2H, J=4.7 Hz), 7.23 (m, 4H), 7.05 (t, 4H, J=7.8 Hz), 6.75 (m, 1H), 4.05 (m, 1H), 3.19 (s, 1H), 2.71 (m, 1H), 2.53 (m, 1H) 2.25 (m, 3H), 1.8 (m, 9H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][C:17]=2[O:25][CH3:26])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[C:3]1=[O:15].Cl.O>C(O)C.[Fe]>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10](=[O:11])[C:2]([OH:1])([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][C:17]=1[O:25][CH3:26])[C:3]2=[O:15]
Reactant: COc1cc(C(C)C)ccc1C1(O)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2cccc(N)c2C1=O
Yield: 70.3 %

Procedure:
2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (52 mg, 1.4 mmol) was completely dissolved in anhydrous ethanol (10 ml). This solution was added with iron (0.59 g, 10.6 mmol), conc. HCl (0.01 ml) and water (1 ml). The reaction mixture was heated for 3 hrs under reflux. After filtration at high temperature to remove iron, the filtrate was concentrated in a vacuum and purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.32 g, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1B(O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: Cc1cnc(Br)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cnc(-c2cc(F)ccc2F)cc1N
Temperature: 95 °C

Procedure:
Bis(triphenylphosphine)palladium chloride (0.927 g, 1.321 mmol), 2-bromo-5-methylpyridin-4-amine (2.47 g, 13.21 mmol), sodium carbonate (6.60 mL, 13.21 mmol) and 2,5-difluorophenylboronic acid (2.71 g, 17.17 mmol) were combined and heated at 95° C. overnight. The reaction was cooled and filtered through a pad of Celite®, rinsed with dioxane (3×50 mL) and the filtrate was concentrated directly onto silica gel and then purified by column chromatography on NH silica eluted with 0-100% ethyl acetate/hexanes to give 2-(2,5-difluorophenyl)-5-methylpyridin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (3H, s) 5.96 (2H, s) 7.04 (1H, d, J=2.02 Hz) 7.20-7.29 (1H, m) 7.29-7.38 (1H, m) 7.68 (1H, ddd, J=9.73, 6.19, 3.28 Hz) 8.02 (1H, s). MS [M+H] found 221.2
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][CH:41]([OH:43])[CH3:42]>>[OH:43][CH:41]([CH3:42])[CH2:40][NH:39][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH:31]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 45.9 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 27 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[CH3:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>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.CN(C=O)C>[CH3:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH:5]=[N:6][CH:7]=2)[CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Reactant: Cc1ccc(B(O)O)cc1C
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: [K+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2cncc(NC(=O)c3ccccc3)c2)cc1C
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 4.5 g (16.2 mmol) of N-(5-bromopyridin-3-yl)benzamide, 3.0 g (19.5 mmol) of (3,4-dimethylphenyl)boronic acid and 4.5 g (32.5 mmol) of potassium carbonate were dissolved in 59 ml of 1,2-dimethoxyethane, 19 ml of water and 117 ml of DMF. The mixture was flushed with argon, 0.1 g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated and purified by column chromatography on silica gel (dichloromethane/methanol 100:1→100:4).
Reaction SMILES: [O-2].[Ca+2:2].[C:3]([OH:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([OH:13])=[O:12])([C:7]([OH:9])=[O:8])[OH:6]>C(O)C>[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Ca+2:2].[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Ca+2:2].[Ca+2:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: CCO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reaction time: 2 h
Yield: 97.8 %

Procedure:
13.4 grams (0.24 Mole) of calcium oxide and 30 grams (0.16 Mole) of citric acid were placed into a beaker provided with a reflux condenser. 80 ml ethanol was added and the mixture was stirred and boiled at atmospheric pressure for 2 hours. The reaction mixture was cooled and thereafter filtered yielding 39 grams of calcium citrate having the physical characteristic of a fine white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([C:15]1[CH:24]=[CH:23][C:18]([CH2:19][NH:20][O:21][CH3:22])=[CH:17][CH:16]=1)#[N:14]>>[C:13]([C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]([O:21][CH3:22])[C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)=[CH:17][CH:16]=1)#[N:14]
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(C#N)cc1
Product: CON(Cc1ccc(C#N)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 99 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-cyanobenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (99% yield): mp 148-149° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.72 (3H, s, OCH3), 4.86 (2H, s, NCH2), 6.39 (1H, s, CH), 7.46 (2H, m, aromatics), 7.63 (2H, m, aromatics). Anal. calcd. for C16H16N2O5: C, 60.75; H, 5.10; N, 8.86. Found: C, 60.60; H, 4.91; N, 8.78.
Reaction SMILES: Cl.[N:2]1[C:7]2[NH:8][CH:9]=[CH:10][C:6]=2[C:5]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[N:4][CH:3]=1.[CH:17](=O)[CH2:18][CH3:19]>C1COCC1>[CH2:17]([NH:16][C@@H:13]1[CH2:14][CH2:15][N:11]([C:5]2[C:6]3[CH:10]=[CH:9][NH:8][C:7]=3[N:2]=[CH:3][N:4]=2)[CH2:12]1)[CH2:18][CH3:19]
Reactant: N[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: CCC=O
Agent: Cl
Solvent: C1CCOC1
Product: CCCN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C

Procedure:
A mixture of (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine hydrochloride (50 mg, 0.24 mmol), propionaldehyde (15 mg, 0.26 mmol) and NaBH(OAC)3 (61 mg, 1.2 mmol) in THF (5 mL) was stirred at the ambient temperature for minutes. It was then quenched with water (2 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (3×5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound. MS (m/z): 246 (M+H)+.
Reaction SMILES: [Br:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O[C@@H]1c2ccccc2C[C@H]1Br
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: BrC1=Cc2ccccc2C1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A 500 mL flask was charged with 25.5 g (120 mmol) of trans-2-bromo-1-indanol, 1 g of toluenesulfonic acid and 350 mL of toluene. This was capped with a Dean-Stark trap and heated to reflux for two hours at which time the system was cooled to room temperature and the volatiles removed in vacuo to leave a dark oil. The residue was taken up into hexanes and eluted through a silica pad using hexanes. Removal of the volatiles in vacuo gave 22.5 g (96 percent) of a light yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:25]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifuluoroacetic acid) salt (EXAMPLE 34 Step 1) and 3-trifluoromethylbenzoic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]=[C:12]=[O:13].[H-].[Na+].[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.C1COCC1.O>[CH3:10][NH:11][C:12](=[O:13])[O:9][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1
Reactant: CN=C=O
Reactant: OCc1cccc(Br)n1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)OCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(6-Bromopyridin-2-yl)methanol (1.5 g, 7.98 mmol) and DMAP (0.097 g, 0.798 mmol) were taken up in THF (20 mL) and cooled to 0° C. Methyl isocyanate (0.501 g, 8.78 mmol) was added before warming to room temperature and stirring overnight. The reaction mixture was cooled to 0° C. and sodium hydride (0.319 g, 7.98 mmol) was added. After 30 minutes at 0° C., water was added followed by saturated NH4Cl and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (6-50% EtOAc-hexanes) gave the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.I[CH2:13][CH2:14][CH3:15].[BH4-].[Na+]>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH2:14][CH3:15])[CH2:7]2
Reactant: Nc1cccc2cnccc12
Reactant: CCCI
Agent: [BH4-]
Agent: [Na+]
Product: CCCN1CCc2c(N)cccc2C1

Procedure:
The title compound was prepared by treatment of 5-aminoisoquinoline with iodopropane followed by reduction with sodium borohydride using procedures analogous to those described in Preparation 1 and Preparation 2.
Reaction SMILES: [K:1].[C:2]1([S:8]([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[CH:14]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[K+].[H][H]>[Pd].CO>[K:1].[C:2]1([S:8]([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[CH:14]=2)(=[O:9])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccc([N+](=O)[O-])c(NCc2ccc(-c3ccccc3)cc2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Yield: 78.2 %

Procedure:
Five-percent palladium on carbon (0.64 g) was added to a mixture containing 4.27 g of N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-nitrobenzamide potassium salt, 10.7 g of a 20% potassium hydrogencarbonate aqueous solution and 200 ml of methanol, and the mixture was stirred in a hydrogen atmosphere at 35° C. for 14 hours. The crystals precipitated were dissolved in 400 ml of a mixed solution of acetone and water (at a ratio of 5:2). The solid material was separated through filtration. The filtrate was concentrated, and the crystals precipitated were separated through filtration, and were dried to give 3.15 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide potassium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:13]2[CH2:15][CH2:14]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:13]2[CH2:14][CH2:15]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1OC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1OC1CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Methyl 5-chloro-2-cyclopropoxybenzoate was dissolved in THF/H2O (1:1, 400 mL), then sodium hydroxide (16 g, 0.4 mol) was added. The mixture was heated to 60° C. and stirred for 1 hour. The reaction mixture was cooled to room temperature, then the pH was adjusted to 4 using 4N aqueous HCl, resulting in precipitation of the product. The precipitate was collected by filtration and azeotroped with toluene to afford 19 g (96%) of 5-chloro-2-cyclopropoxybenzoic acid. 1H NMR (400 MHz, CDCl3) δ: 12.96 (br, 1H), 7.58 (m, 2H), 7.43 (q, 1H), 3.91 (m, 1H), 0.81 (m, 4H).
Reaction SMILES: O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].O.[I:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([NH:23]C(=O)OCC)[N:22]=2)[N:19]=1>CN1CCCC1=O>[I:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([NH2:23])[N:22]=2)[N:19]=1
Reactant: CCOC(=O)Nc1cn2nc(I)ccc2n1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1cn2nc(I)ccc2n1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
To barium hydroxide octahydrate (14.5 g, 46.1 mmol) was added water (240 mL), and the mixture was stirred at 80° C. for 15 min. A solution of ethyl (6-iodoimidazo[1,2-b]pyridazin-2-yl)carbamate (10.2 g, 30.7 mmol) in N-methylpyrrolidone (80 mL) was added to the mixture, and the mixture was stirred at 120° C. for 8 hr. After cooling the mixture to room temperature, water (480 mL) was added to the mixture, and the mixture was stirred for 1 hr. The mixture was extracted twice with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (6.1 g, 76%) as a brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)C(OC)=O)[CH:6]=1.BrCC1C=C(C=CC=1)C(OC)=O.BrC(C1C=CC=CC=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([C:8]2[CH:17]=[CH:16][CH:15]=[CH:10][CH:9]=2)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:6]=1
Reactant: COC(=O)c1cccc(Cn2cc(Br)cn2)c1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: COC(=O)c1cccc(CBr)c1
Product: CCOC(=O)C(c1ccccc1)n1cc(Br)cn1

Procedure:
The title compound was prepared using a procedure analogous to methyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzoate except that methyl 3-(bromomethyl)benzoate was replaced with ethyl 2-bromo-2-phenylacetate. LCMS, [M+H]+=308.9. 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.45-7.36 (m, 6H), 6.14 (s, 1H), 4.34-4.23 (m, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 15 h
Yield: 77.1 %

Procedure:
To a solution of 4-amino-2,6-dichloropyridine (1.07 g, 6.56 mmol) in conc H2SO4 (3.5 mL) was added 0.50 mL of 70% HNO3 (7.94 mmol) at room temperature. The mixture was stirred at 55° C. for 15 h, then poured into ice-H2O (70 mL). To this mixture was added 40% aq. NaOH slowly to adjust the pH to 10. The precipitate was filtered, washed with water and dried to give 1.052 g (77%) of 23 as a pale yellow powder, mp 136°-8° C. 1H NMR (CDCl3) δ 6.116 (bs, 2H), 6.750 (s, 1H). It was used for the next reaction without further purification.