Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:25]2[CH:30]=[CH:29][C:28]([N:31]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=O)=O.[Br-:48].[Li+].O1CCCC1>O>[Br:48][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:25]2[CH:30]=[CH:29][C:28]([N:31]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCOS(C)(=O)=O)cc3)cc2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCBr)cc3)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a dry schlenk flask was added 3-(4-((4-(bis(4-methoxyphenyl)amino)phenyl)(4-methoxyphenyl)amino)phenoxy)propyl methanesulfonate (4.06 g, 6.20 mmol). The flask was evacuated under vacuum and filled with nitrogen. Lithium bromide (5.39 g; 62.0 mmol) and tetrahydrofuran (6.2 mL) were added under nitrogen. The mixture was allowed to stir at 60° C. overnight. Upon disappearance of the starting material the reaction mixture was poured into a separatory funnel containing 100 mL of cold water. The product was extracted using 3×50 mL ether. The organic layers were combined and washed with 3×50 mL of water. The resulting ether layers were dried over Na2SO4. The drying agent was removed by filtration and the solvent was removed under reduced pressure. The residual solvent was removed in vacuo (3.12 g, 78.2%). 1H NMR (400 MHz, C3D6O) δ 6.97 (m, 8H), 6.86 (m, 8H), 6.80 (s, 4H), 4.09 (t, J=5.9 Hz, 2H), 3.75 (s, 9H), 3.66 (t, J=6.6 Hz, 2H), 2.28 (q, J=6.2 Hz, 2H). 13C{1H} NMR (400 MHz, C3D6O) δ 156.39, 155.34, 143.71, 143.51, 142.22, 127.05, 126.27, 126.03, 123.90, 123.70, 116.10, 115.40, 114.61, 66.34, 55.62, 33.25, 31.05. HRMS-EI (m/z): [M]+ calcd for C36H35BrN2O4, 640.18; found, 640.1). Anal. Calcd for C36H35BrN2O4: C, 67.60; H, 5.52; N, 4.38. Found: C, 67.43; H, 5.61; N, 4.24.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.[C:10]([CH2:14][C:15](OC)=[O:16])(=O)[CH2:11][CH3:12]>O>[CH2:11]([C:10]1[C:7]2[C:6](=[O:8])[NH:5][C:4](=[S:9])[NH:3][C:2]=2[O:1][C:15](=[O:16])[CH:14]=1)[CH3:12]
Reactant: CCC(=O)CC(=O)OC
Reactant: Oc1cc(O)nc(S)n1
Solvent: O
Product: CCc1cc(=O)oc2[nH]c(=S)[nH]c(=O)c12
Yield: 37.3 %

Procedure:
A mixture of 4,6-dihydroxy-2-mercapto-pyrimidine (20.0 g, 138.7 mmol) and methyl propionylacetate (21.8 mL, 173.4 mmol) was heated at 165° C. until the ester was completely reacted. The reaction mixture was cooled down and poured into water (75 mL) and then filtered through a sintered funnel. The solid residue was washed with water (2×20 mL) and dried under vacuum to yield 5-ethyl-2-thioxo-2,3-dihydro-1h-pyrano[2,3-d]pyrimidine-4,7-dione (11.6 g, 37%).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][N:3]=1.[NH2:8][C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=1.Cl[C:16]1[C:17]2[N:25]=[C:24](Cl)[CH:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[CH3:7][C:5]1[NH:6][C:2]([S:1][C:24]2[CH:23]=[CH:22][C:18]3[N:19]=[CH:20][N:21]=[C:16]([NH:8][C:9]4[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=4)[C:17]=3[N:25]=2)=[N:3][N:4]=1
Reactant: Cn1ccc(N)n1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Cc1nnc(S)[nH]1
Product: Cc1nnc(Sc2ccc3ncnc(Nc4ccn(C)n4)c3n2)[nH]1

Procedure:
The compound of Example 58 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 3-mercapto-5-methyl-4H-[1,2,4]triazole, 3-amino-1-methyl-1H-pyrazole and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: [C:1]1([C:7]2([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:19]3[CH:18]=[C:17]([Br:20])[CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][C:10]([Br:21])=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][Br:36])=[CH:26][CH:27]=3)[C:8]3[CH:9]=[C:10]([Br:21])[CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2(c3ccccc3)c3cc(Br)ccc3-c3ccc(Br)cc32)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(C2(c3ccccc3)c3cc(Br)ccc3-c3ccc(Br)cc32)cc1
Yield: 89.8 %

Procedure:
Into a flask, 9-phenyl-9-(4-methylphenyl)-2,7-dibromofluorene (0.90 g, 1.84 mmol), NBS (0.33 g, 1.84 mmol), BPO (0.044 g, 0.184 mmol) and CCl4 (10 ml) were added and reacted under reflux for 2 hr. Then, the reaction system was cooled and filtered. After removing the filtrate, a gray solid of 9-phenyl-9-(4-bromomethylphenyl)-2,7-dibromofluorene (0.94 g) was obtained as a pure intermediate product (yield, 90%). 1HNMR (300 MHz, CDCl3): δ 7.51-7.48 (m, 6H), 7.26-7.00 (M, 9H), 4.46 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:17]=1[O:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24])=[CH:21][CH:20]=1>>[Cl:36][C:34]1[CH:33]=[CH:32][C:17]([O:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24])=[CH:21][CH:20]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:35]=1
Reactant: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(C(=O)NCCOC)cc3)ccnc2n1

Procedure:
The product from Example 2g (75 mg, 0.36 mmol) was reacted with the product from Example 126e (116 mg, 0.36 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (101.7 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J=7.35 Hz, 3H) 1.70-1.90 (m, 2H) 2.90-3.01 (m, 2H) 3.24 (s, 3H) 3.32-3.47 (m, 4H) 6.73 (d, J=6.99 Hz, 1H) 6.98 (d, J=8.82 Hz, 2H) 7.29 (d, J=8.82 Hz, 1H) 7.61 (dd, J=8.82, 2.57 Hz, 1H) 7.71-7.81 (m, 4H) 8.42 (t, J=4.78 Hz, 1H) 8.53 (d, J=6.99 Hz, 1H) 8.85 (d, J=8.82 Hz, 1H) 10.92 (s, 1H) 14.57 (s, 1H); MS (ESI+) m/z 491 (M+H−TFA)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10]/[CH:11]=[C:12](/[CH2:16][CH2:17][CH2:18][F:19])\[C:13]([OH:15])=[O:14])=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[NH2:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10]/[CH:11]=[C:12](/[CH2:16][CH2:17][CH2:18][F:19])\[C:13]([OH:15])=[O:14].[F:23][C:24]([F:29])([F:28])[C:25]([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](C/C=C(/CCCF)C(=O)O)C(=O)O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](C/C=C(/CCCF)C(=O)O)C(=O)O
Product: O=C([O-])C(F)(F)F

Procedure:
(Z)—(S)-5-[(tert-Butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioic acid (10.0 mg, 0.03 mmol) was stirred in a mixture of trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL) at r.t. for 4 h. After that the mixture was concentrated under reduced pressure, the residue was taken up in water (10 mL) and the solution was lyophilised. Yield: 6.0 mg, 0.02 mmol, 56%.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11](=[O:12])[CH:13]=[CH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH3:4]
Reactant: Cc1ccccc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C=CC(=O)C=Cc1ccccc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.3 %

Procedure:
2-Methylbenzaldehyde (1ac, 1.45 ml, 12.5 mmol) and acetone (19, 0.46 ml, 6.3 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (2.61 g, 65.3 mmol) and water (25 ml) was added and the mixture stirred for 3 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethanol to give 0.71 g (43%) of a yellow solid: mp 98-100° C. [expected mp 94-96° C.]; 1H NMR: δ 2.47 (s, 6H), 6.98 (d, 2H, J=15.9 Hz), 7.24 (m, 6H), 7.64 (d, 2H, J=7.2 Hz), 8.03 (d, 2H, J=15.9 Hz); 13C NMR: δ 19.7, 126.1, 126.2, 126.5, 129.9, 130.7, 133.6, 137.9, 140.5, 188.5.
Reaction SMILES: C1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)CC1.[F:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].[C:24](=O)([O-])[O-].[Li+].[Li+]>>[F:13][C:14]1[C:21]([CH3:22])=[C:20]([N:6]2[C@H:7]([CH3:24])[CH2:8][C@H:4]([OH:12])[C@@H:5]2[CH3:9])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: Cc1c(F)ccc(C#N)c1F
Reactant: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1c(N2[C@H](C)C[C@H](O)[C@@H]2C)ccc(C#N)c1F

Procedure:
By an operation in the same manner as in Example 53 and using (2S,3S,5R)-2,5-dimethylpyrrolidin-3-ol 0.5 oxalate (189 mg), 2,4-difluoro-3-methylbenzonitrile (510 mg) and lithium carbonate (200 mg), the title compound was obtained as colorless oil (yield: 20 mg, yield: 6.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41](O)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(OC)cc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.7 %

Procedure:
p-Methoxyaniline (0.104 g, 0.845 mmol), triethylamine (0.085 g, 0.845 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.143 g, 0.845 mmol) were added to a methylene chloride solution (20 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.158 g, 0.422 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=30:1) and then recrystallized from isopropyl ether to obtain the titled compound (0.066 g, 0.138 mmol, 33%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:15]([NH:17][O:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(NCC2C=CSC=2)CC1)=O)(C)(C)C.[O:46]=[C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49](=[O:56])[N:48]1[CH2:57][CH2:58]C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)(=O)C>[O:46]=[C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49](=[O:56])[N:48]1[CH2:57][CH2:58][CH2:6][N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:15]([NH:17][O:18][CH3:19])=[O:16])[CH2:12][CH2:13]1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Reactant: CONC(=O)N(Cc1ccsc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC(NCc2ccsc2)CC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CONC(=O)N(Cc1ccsc1)C1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
4-(3-Methoxy-1-thiophen-3-ylmethyl-ureido)-piperidine-1-carboxylic acid tert-butyl ester (0.950 g, 2.69 mmol) was dissolved in a 3:1 mixture of CH2Cl2 and TFA and the mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the resulting brown oil pumped in vacuo (high vacuum system) for 2 h. Using general procedure A, the crude amine, 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (0.561 g, 2.75 mmol), acetic acid (20 drops, cat.) and sodium triacetoxyborohydride (0.792 g, 3.75 mmol) were combined in CH2Cl2 (40 ml) and the resulting mixture was stirred at rt for 16 h. Standard basic workup gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 94:5:1, v/v/v) gave 1-{1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-3-methoxy-1-thiophen-3-ylmethyl-urea as a white foam (0.692 g, 62%). 1H NMR (CDCl3) δ 1.36 (m, 2H), 1.59 (m, 2H), 1.85 (p, 2H, J=4.5 Hz), 1.91 (t, 2H, J=9.0 Hz), 2.39 (t, 2H, J=6.0 Hz), 2.88 (d, 2H, J=12.0 Hz), 3.62 (s, 3H), 3.75 (t, 2H, J=6.0 Hz), 4.04 (s, 2H), 4.23 (m, 1H), 6.90 (d, 1H, J=3.0 Hz), 6.99 (s, 1H), 7.06 (s, 1H), 7.36 (m, 1H), 7.62 (m, 2H), 7.81 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC1C=CC(C)=CC=1.[C:21]([NH2:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)O>CC(N(C)C)=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]2[O:9][C:28]3[CH:27]=[CH:26][CH:25]=[CH:23][C:22]=3[C:21](=[O:29])[N:30]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccccc1O
Solvent: Cc1ccc(C)cc1
Solvent: CC(=O)N(C)C
Product: O=c1nc(-c2ccc([N+](=O)[O-])cc2)oc2ccccc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 100.2 %

Procedure:
36.6 g of 4-nitrobenzoyl chloride are added to 48 g of p-xylene over 5 minutes and the suspension warmed to 80° C. To this suspension is then added, over 90 minutes, at 80° C., a solution of 13.2 g of salicylic acid amide in 7.2 g of dimethylacetamide, with stirring. The temperature is then raised to 135° C. over 1 hour and the mixture stirred at this temperature for a further 6 hours. After this time, the mixture is treated with 48 g of p-xylene, cooled to 80° C., the precipitated solids filtered, washed with p-xylene and dried, to yield 25.87 g of 2-(4-nitrophenyl)-4H-1,3-benzoxazin-4-one melting at 249-251° C. and having the following elemental analysis:
Reaction SMILES: Cl[C:2]1[NH:3][S:4](=[O:17])(=[O:16])[C:5]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH2:26][NH:25][CH2:24][CH2:23]2>COC(O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH2:26][N:25]([C:2]1[NH:3][S:4](=[O:17])(=[O:16])[C:5]3[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:6]=3[N:7]=1)[CH2:24][CH2:23]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1cc2c(cc1OC)S(=O)(=O)NC(Cl)=N2
Agent: COC(C)O
Product: COc1cc2c(cc1OC)CN(C1=Nc3cc(OC)c(OC)cc3S(=O)(=O)N1)CC2
Yield: 50.3 %

Procedure:
3-Chloro-6,7-dimethoxy-2H-benzo[1,2,4]thiadiazine-1,1-dioxide 1a (154 mg, 0.55 mmol) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 2a (wherein R1 and R4 are hydrogen, and R2 and R3 are methoxy) (138 mg, 0.6 mmol) were dissolved in 20 ml of methoxyethanol and heated at reflux for 72 h. The solvent was removed under reduced pressure. The gummy residue was triturated with isopropanol and the resulting crystals filtered. Recrystallization from dichloromethane afforded 120 mg of 3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-2H-benzo[1,2,4]thiadiazine-1,1-dioxide 101, [M+H]+=434.
Reaction SMILES: C([C:3]1[CH:8]([CH3:9])[CH:7]=[CH:6][N:5]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:4]=1)=O.CN(C=O)C.P(Cl)(Cl)(Cl)=O.CN(C=O)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH3:9][CH:8]1[CH:7]=[CH:6][N:5]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:4]=[CH:3]1
Reactant: CC1C=CN(C(=O)Oc2ccccc2)C=C1C=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1C=CN(C(=O)Oc2ccccc2)C=C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a dry 500 ml three neck flask under nitrogen, a solution of cuprous iodide (0.28 g, 1.5 mmol) and dimethyl sulfide (8 ml) in 30 ml of dry THF was stirred at room temperature for 10 minutes. Pyridine (2.43 ml, 30 mmol) in 120 ml of dry THF was added to the reaction, then cooled to -25° C. Phenylchloroformate (3.9 ml, 30 mmol) in 10 ml dry THF was added to the reaction via an addition funnel (a thick brown precipitate formed immediately upon addition). The mixture was stirred for 15 minutes. Methyl magnesium chloride (10 ml, 30 mmol) was added to the mixture via syringe whereupon the brown precipitate dissolved. The reaction was stirred at -25° C. for 20 minutes then stirred at room temperature for 20 minutes. 20% NH4Cl(aq) (70 ml) was added to the reaction. The mixture was then extracted with 150 ml diethyl ether. The organic extract was then washed with 40 ml portions of 20% NH4 Cl(aq) /NH4OH (1:1), water, 10% HCl(aq), water, and brine. The organic layer was then dried over NaCl/Na2SO4, filtered, and concentrated to yield 5.9 g of a yellow oil. Kugelrohr distillation (bp. 150°-170° C., 1 mmHg) to yield 4.9 g (77%) of the desired compound (A). B. 3-Formyl-4-methyl-1-(phenoxycarbonyl)-1,4-dihydropyridine To a dry 50 ml flask under nitrogen, DMF (7.44 ml, 97 mmol) in 10 ml of dichloromethane was cooled to 0° C. Phosphorus oxychloride (4.5 ml, 48 mmol) was slowly added to the solution. The solution was stirred at room temperature for 30 minutes. (A) (4.7 g, 22 mmol) in 40 ml of dichloromethane was stirred in a 100 ml two neck flask under nitrogen at 0° C. The DMF/Phosphorus oxychloride solution was transferred to an addition funnel via cannula then slowly added to the (A)/dichloromethane solution. The ice bath was then removed, and the reaction was stirred at room temperature for 20 hours. The reaction was cooled to 0° C. whereupon a solution of potassium acetate (15 g) in 50 ml of water was carefully added via the addition funnel. The mixture was then allowed to reflux for 20 minutes. The methylene chloride layer was separated then extracted once more with 100 ml methylene chloride. The organic phases were combined then washed with 40 ml portions of water, K2CO3(aq), water and brine, then dried over NaCl/Na2SO4. The organics were concentrated on a rotary evaporator to yield 4 g of a brown oil. Purified by flash chromatography over silica gel eluting with ethyl acetate/hexane. Yield 2.0 g (37%) of the desired compound (B).
Reaction SMILES: C(OC([N:8]([CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=2[C:35]#[N:36])[CH2:21][CH2:20]1)[C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:37].C(OCC)C>C(Cl)Cl>[ClH:37].[ClH:37].[C:35]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:26]=1[CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:8][C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:20][CH2:21]1)[C:30]([OH:32])=[O:31])#[N:36]
Reactant: CC(C)(C)OC(=O)N(CC1CCN(Cc2ccc(C(=O)O)cc2C#N)CC1)[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1cc(C(=O)O)ccc1CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a stirred solution of 4-((4-(((tert-butoxycarbonyl)((trans)-2-phenylcyclopropyl)amino) methyl)piperidin-1-yl)methyl)-3-cyanobenzoic acid (400 mg, 0.817 mmol) in DCM (5 mL) was added HCl in diethyl ether (5 mL, 0.817 mmol) at 0° C. and stirred at RT for 2 h. The reaction mixture was concentrated and the residue was triturated with diethyl ether (2×10 mL) and dried to afford 3-cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid, dihydrochloride (250 mg, 0.538 mmol, 65.9% yield) as white solid. LCMS (ES) m/z: 390.09 (M+H)+. 1HNMR (400 MHz in D2O): δ 8.489 (bs, 1H) 8.342 (d, J=8 Hz, 1H), 7.866 (d, J=8 Hz, 1H), 7.400-7.291 (m, 3H), 7.209 (d, J=8 Hz, 2H), 4.624 (s, 2H), 3.683 (d, J=10.8 Hz, 2H), 3.269-3.214 (m, 4H), 2.979-2.997 (m, 1H), 2.526-2.577 (m, 1H), 2.107 (d, J=14.8, 3H), 1.528-1.618 (m, 3H), 1.434 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=[O:12].[Na+].[Na+].CN[C@@H]1CCCC[C@H]1NC.Cl>CN[C@@H]1CCCC[C@H]1NC.O>[OH:12][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=C([O-])[O-]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
Under nitrogen, 7.82 g (50 mmol) of 2-chlorobenzoic acid was combined with 31 g of H2O. 6.62 g (62.5 mmol) of Na2CO3 was then added. The mixture was heated to reflux with stirring for 30 min, remaining under a nitrogen atmosphere. Separately, 36 mg of CuBr and 79 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 1 mL H2O under nitrogen. The resulting mixture was stirred under an air atmosphere until the CuBr was dissolved to give a deep purple solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for bout 3 h at 100° C. and the reaction was monitored by 1H NMR. Table 3 shows the distribution of starting material and product at different reaction times. A product selectivity of more than 99% was observed. After reaction completion, the mixture was allowed to cool to 25° C. and the reaction mixture was acidified with 15% HCl, producing a white precipitate. The white precipitate was filtered, washed with water and dried yielding 6.00 g 2-hydroxybenzoic acid (85% yield). The filtrate was extracted with ethyl acetate and evaporated to dryness to receive another 0.65 g of 2-hydroxybenzoic acid resulting in a total yield of 6.65 g (48.2 mmol, 96% yield).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[C:10](=[O:20])[NH:9][N:8]=1.[CH3:21][CH2:22]O>>[CH2:21]([O:18][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([Br:6])=[N:8][NH:9][C:10]2=[O:20])=[O:19])[CH3:22]
Reactant: O=C(O)c1ccc2c(Br)n[nH]c(=O)c2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(Br)n[nH]c(=O)c2c1
Yield: 31 %

Procedure:
Concentrated sulfuric acid (40 ml) was added to a stirred solution of 1-bromo-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (85 g, 0.32 mol) in EtOH (500 ml) and the mixture was heated to reflux for 48 hours. After this time, the reaction mixture was cooled and the resulting precipitate was filtered. The precipitate was partitioned between EtOAc (1 L) and saturated NaHCO3 (500 ml), the organic layer was separated and washed with water (500 ml) before being dried (MgSO4), filtered and concentrated under vacuum to give the title compound (30 g, 31% yield) as a white solid. Tr=1.23 min, m/z (ES+) (M+H)+ 297 & 299
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:29][NH2:30]>>[CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:24])([F:25])[F:26])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:14]([NH:30][CH3:29])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CN
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Agent: Cl
Product: CNC(=O)C(NC(=O)c1cc(O[C@@H](C)C(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and methanamine hydrochloride as starting materials and isolated (28 mg, 54%); MS (ESI, m/z): 402.6 (M+H+).