Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)C2C(C3C(C=2)=CC=CC=3)=CC=C1.[NH2:29][C:30]1[N:31]=[C:32]([NH2:41])[C:33]2[CH:39]=[C:38](N)[CH:37]=[N:36][C:34]=2[N:35]=1.CCN(CC)CC>>[NH2:29][C:30]1[N:31]=[C:32]([NH2:41])[C:33]2[CH:39]=[C:38]([NH:14][CH:1]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:7]4[C:2]3=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:37]=[N:36][C:34]=2[N:35]=1
Reactant: Nc1cnc2nc(N)nc(N)c2c1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C1C=CC=C2C1=Cc1ccccc12
Solvent: CCN(CC)CC
Product: Nc1nc(N)c2cc(NC3c4ccccc4-c4ccccc43)cnc2n1

Procedure:
9-[N-(2,4-Diaminopyrido[2,3-d]pyrimidin-6-yl)amino]fluorene (Formula I: Ar=2,4-diaminopyrido[2,3-d]pyrimidin-6-yl; W=NH; X=CH; Z=chemical bond; m=n=0) is prepared similarly to N-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)amino]benzhydrylamine as disclosed above by using fluorenone (360 mg, 2.0 mmol), 2,4,6-triaminopyrido[2,3-d]pyrimidine (350 mmol), mg, 2.0 mmol), and BH3.Et3N (75 mg, 6.6 mmol). The product can be purified by chromatography.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-])=O)=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:14][C@@H:15]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:16])=[CH:4][CH:3]=1.C(O)(=O)C>[Fe].O>[NH2:11][C:10]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH2:14][C@@H:15]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:16])[N:7]=[CH:6]2
Reactant: C[C@@H](Cn1ncc2ccc(O)c([N+](=O)[O-])c21)NC(=O)OCc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](Cn1ncc2ccc(O)c(N)c21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step C (0.20 g, 0.54 mmol) was combined with acetic acid (5 mL), water (5 mL), and iron powder (0.30 g mmol) and stirred at room temperature for 1 h. The reaction mixture was filtered and evaporated to a dark oil (0.47 g) which was was used in the next reaction: LC/MS m/z 341.
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][C:16](=[CH:19][C:20]#[N:21])[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2>O1CCCC1.[C].[Pd]>[C:1]1([C@@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][C:20]#[N:21])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][C:20]#[N:21])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: N#CC=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: N#CC[C@H]1CC[C@@H](c2nnn3cnc4[nH]ccc4c23)CC1
Product: N#CC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Yield: 6 %

Procedure:
2-[4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetonitrile (20.0 mg, 0.0720 mmol) in tetrahydrofuran (10 mL) were stirred with 5% palladium-carbon (10 mg) at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (hexane/ethyl acetate=1/1 (v/v)) to give 2-[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acetonitrile (Synthetic Examplea 435a; colorless solid, 1.30 mg, yield 6%) in a less polar fraction and 2-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]acetonitrile (Synthetic Examplea 435b; colorless solid, 3.40 mg, yield 17%) in a more polar fraction.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]([CH2:47]OCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:9]=1/[CH:42]=C\OCC.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].O>>[C:23]1([C:20]2[N:19]=[CH:18][C:17]([C:16]3[CH:15]=[N:14][N:13]4[C:8]5[NH:7][CH:47]=[CH:42][C:9]=5[C:10]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[N:11][C:12]=34)=[CH:22][CH:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]
Reactant: CCO/C=C\c1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1ccc(-c2ccc(-c3cnn4c3nc(C3CCNCC3)c3cc[nH]c34)cn2)cc1
Reaction time: 8 h

Procedure:
(Z)-tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(2-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-15a, 330 mg) was treated with TFA/water (1:1, 4 mL), stirred overnight, concentrated and lyophilized to provide the title compound as a TFA salt
Reaction SMILES: Cl[CH2:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C([O-])(=[S:11])C.[K+].[I-].[K+].[CH2:16]([OH:18])[CH3:17]>>[C:16]([CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:5])=[S:11])(=[O:18])[CH3:17]
Reactant: CC(C)(CCl)C(=O)O
Reactant: CC([O-])=S
Reactant: CCO
Agent: [I-]
Agent: [K+]
Product: CC(=O)CC(C)(C)C(O)=S
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: The mixture of 50 g of 3-chloropivalic acid, 4.2 g of potassium thioacetate, 1 g of potassium iodide and 200 ml of ethanol is refluxed for 18 hours. It is cooled to room temperature, filtered, the filtrate evaporated and the residue partitioned between 100 ml of water and 200 ml of diethyl ether. The aqueous layer is extracted with 100 ml of diethyl ether, the combined organic layers dried, evaporated and the residue distilled at 150°-155°/3 mm Hg, to yield the 3-acetylthiopivalic acid.
Reaction SMILES: [C:1]([O:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19](=[O:21])[CH3:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[OH-].[K+].OS(O)(=O)=O.CC(O)=O>N1C=CC=CC=1>[N+:16]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[O:9][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH:20][C:19]2=[O:21])([O-:18])=[O:17]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1OC(=O)c1cccnc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=c1cc(-c2cccnc2)oc2c([N+](=O)[O-])cccc12
Temperature: 50 °C
Yield: 34.7 %

Procedure:
2-acetyl-6-nitrophenyl nicotinate 5 (1.3 g, 4.4 mmol) was dissolved in pyridine (10 mL) and heated to 50° C. Finely powdered KOH (3.4 g, 6.1 mmol) was added in small portions. After cooling to room temperature the reaction mixture was concentrated to dryness. Concentrated H2SO4 (0.4 g, 4.4 mmol) and AcOH (3 mL) was added and the mixture was heated to 80° C. for 2 h. The reaction mixture was concentrated to dryness and the crude residue was purified by flash chromatography eluting with Pentane/EtOAc (5:1) to give 6 (410 mg, 35% yield).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][NH:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCC1>C(O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[C:18](=[CH:22][CH2:23][CH2:24][CH3:25])[NH:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1CNC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNC1
Solvent: CCO
Product: CCCC=C1NC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.00 g (3.29 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-ylthio)butyl]hydantoin and 0.30 ml (3.29 mmol) of n-butyraldehyde in 10 ml of ethanol, 0.05 ml (0.6 mmol) of pyrrolidine was added, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate/ethanol=10/1→chloroform/methanol=10/1) to yield 0.43 g (36.5%, orange-yellow oily substance) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:9]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5([NH:27]C(=O)OC(C)(C)C)[CH2:24][C:23]([F:26])([F:25])[CH2:22]5)=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH2:27][C:21]1([C:18]2[CH:17]=[CH:16][C:15]([C:9]3[C:8]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:7][C:6]4[C:5]5=[N:4][N:3]=[C:2]([NH2:1])[N:14]5[CH:13]=[CH:12][C:11]=4[N:10]=3)=[CH:20][CH:19]=2)[CH2:24][C:23]([F:25])([F:26])[CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(N)nnc5c4cc3-c3ccccc3)cc2)CC(F)(F)C1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(N)CC(F)(F)C5)cc4)nc3ccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of {1-[4-(3-amino-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]-3,3-difluorocyclobutyl}carbamate (5-18) (4 mg, 0.007 mmol) in CHCl3 (0.5 mL) was added TFA (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were free based by suspending in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 8-[4-(1-amino-3,3-difluorocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-amine (5-19) as a yellow oil. HRMS (M+H)+: observed=443.1796, calculated=443.1801.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[N:14]1[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]1
Reactant: Fc1cncc(Cl)c1I
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCN(c2c(F)cncc2Cl)CC1

Procedure:
A solution of 3-chloro-5-fluoro-4-iodo-pyridine (2.18 g, 8.468 mmol), 1-methylpiperazine (1.272 g, 1.409 mL, 12.70 mmol) and DIPEA (2.189 g, 2.950 mL, 16.94 mmol) in MeCN (13.08 mL) was heated at 130° C. in the microwave for 300 min. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica eluting with 0-10% MeOH/DCM. Product fractions were combined and concentrated in vacuo to leave 1-(3-chloro-5-fluoropyridin-4-yl)-4-methylpiperazine as a yellow/brown oil. (1.16 g, 59%). MS (ES+) 230.0.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[CH:11][C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1.CN(C=O)C.[Br:40]N1C(=O)CCC1=O>O>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11]([Br:40])[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:27])([CH3:28])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)C2=C(C=C3C=CC(c4ccc(-c5ccccc5)cc4)C=C32)C=C2N=c3ccccc3=C21
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Temperature: 70 °C
Reaction time: 7 h
Yield: 69.5 %

Procedure:
The resulting 10-(biphenyl-4-yl)-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (42.5 g) and DMF (2.5 L) were added to a reaction vessel, and the mixture was heated up to 70° C. and dissolved. After cooled to a room temperature, N-bromo-succinimide (17.4 g) was added, and the mixture was stirred for 7 hours. Water (2.5 L) was added, and filtration was performed to obtain a white powder of 10-(biphenyl-4-yl)-7-bromo-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (34.9 g; yield 69.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[NH:9][C:8](=[O:16])[CH2:7]2)[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[C:12]([O:13][CH2:14][CH3:15])[CH:11]=2)[CH2:7][C:8]1=[O:16])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc2c(cc1OCC)NC(=O)C2
Product: CCOc1cc2c(cc1OCC)N(C(C)=O)C(=O)C2

Procedure:
Prepared from 5,6-diethoxy-2-indolinone and acetic anhydride
Reaction SMILES: [CH:1]([S:3]([NH:6][CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)(=[O:5])=[O:4])=[CH2:2].[ClH:17]>CCOC(C)=O>[Cl-:17].[CH:1]([S:3]([NH:6][CH2:7][CH2:8][NH3+:9])(=[O:5])=[O:4])=[CH2:2]
Reactant: Cl
Reactant: C=CS(=O)(=O)NCCNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: C=CS(=O)(=O)NCC[NH3+]
Product: [Cl-]
Reaction time: 1 h

Procedure:
A solution of tert-butyl 2-[(vinylsulfonyl)amino]ethylcarbamate (1.60 g, 6.39 mmol) in EtOAc (55 ml) at 0 C, was saturated with HCl gas and then stirred for 1 hr. The solvent was evaporated in vacuo to afford the product as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:20]2[CH2:22][CH2:21]2)=[C:6]([CH:8]2[C:10]3([C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[O:12][C:11]3([CH3:19])[CH3:18])[O:9]2)[CH:7]=1>ClCCl.[Fe](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:20]2[CH2:21][CH2:22]2)=[C:6]([CH:8]2[C:14](=[O:15])[C:13]([CH3:16])([CH3:17])[O:12][C:11]([CH3:18])([CH3:19])[C:10]2=[O:9])[CH:7]=1
Reactant: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2C2CC2)C1=O
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(Br)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of iron (III) chloride (53.0 g, 327 mmol) in anhydrous dichloromethane (1000 ml) at 5° C. is added a second solution of 2-(5-bromo-2-cyclopropylphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (119.1 g, 326 mmol) in anhydrous dichloromethane (400 ml), at such a rate as to maintain an internal temperature below 10° C. After stirring for 15 minutes the reaction is quenched with distilled water (900 ml) and the mixture is allowed to warm to room temperature. The two phases are separated and the aqueous phase is extracted with dichloromethane (×2). Organics are combined and the crude product is extracted into 1M aqueous potassium carbonate, followed by acidification to pH0 with concentrated hydrochloric acid and re-extraction with dichloromethane. All organics are combined then washed with brine and dried over anhydrous magnesium sulfate. Concentration in vacuo then affords 4-(5-bromo-2-cyclopropylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2O.P(Br)(Br)([Br:17])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Br:17][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[C:10]([CH3:13])[CH:9]=1
Reactant: COc1cccc2c(O)cc(C)nc12
Reactant: O=P(Br)(Br)Br
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1cccc2c(Br)cc(C)nc12
Temperature: 120 °C
Reaction time: 0.67 h

Procedure:
8-Methoxy-2-methyl-quinolin-4-ol (9.0 g, 48 mmol) and POBr3 (53 g, 185 mmol) was placed in a round-bottomed flask, equipped with a drying tube containing P4O10. After stirring for 40 min at 120° C., the reaction mixture was cooled to room temperature and poured on ice. The mixture was then extracted with DCM (2×200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/EA 10:1) to give the title compound. MS (m/z): 252.4 [M+H+].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][C@H:14]([CH:19]([CH3:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16]>>[O:3]1[C:4]2[CH:9]=[C:8]([C:10]([NH:13][C@H:14]([CH:19]([CH3:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16])=[O:12])[CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](N)C(C)C
Product: COC(=O)[C@H](NC(=O)c1ccc2c(c1)OCO2)C(C)C
Yield: 50 %

Procedure:
Prepared in a similar manner to example 4 using benzo[d][1,3]dioxole-5-carboxylic acid and (R)-methyl 2-amino-3-methylbutanoate. Yield: 50%. MS (M+H; 280.1).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=2)[C:12]([O:14]C)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.O.[OH-].[Li+]>C1COCC1.O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=2)[C:12]([OH:14])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OC2CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
Methyl 3-[(phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoate (9.00 g, 26.3 mmol) was dissolved in THF (120 mL) and methanol (30 mL) added a solution of lithium hydroxide monohydrate (3.24 g, 78.9 mmol) in water (60 mL). The bi-phasic solution was stirred at RT for 3 hours until complete conversion was indicated by LCMS. The organics were removed in vacuo and water (40 mL) added. The pH of the mixture was adjusted to 7 by the addition of hydrochloric acid and the resulting precipitate filtered and washed with cold water to give the desired compound as a white solid (8.03 g). 1H NMR δ (d6-DMSO): 1.57 (m, 2H), 1.94 (m, 2H), 3.50 (m, 2H), 3.84 (m, 2H), 4.62 (m, 1H), 5.15 (s, 2H), 6.87 (t, 1H), 7.09 (m, 1H), 7.14 (m, 1H), 7.34 (t, 1H), 7.40 (t, 2H), 7.46 (d, 2H), 12.99 (s, 1H); m/z 327 (M+H)+
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:11][CH2:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccccc1CBr
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 53.7 %

Procedure:
In a 1 L round bottom flask fitted with a reflux condenser, a stirred suspension of 10.00 g of o-toluic acid and 19.56 g (1.5 eq.) N-bromosuccinimide in 735 mL chloroform was sparged for 0.5 h with nitrogen. The sparging was discontinued, and the suspension was stirred and irradiated under nitrogen atmosphere using a 500 W quartz halogen lamp at 75% power, causing the solids to dissolve and the chloroform to reflux. The red color of the reaction mixture disappeared after 1.5 h, and 6.52 g (0.5 eq.) of N-bromosuccinimide was added. The reaction mixture was stirred and irradiated under nitrogen atmosphere with a 500 W quartz halogen lamp at 75% power for another 1.5 h, at which time the solution became colorless. The solvent volume was reduced in vacuo to about 100 mL, and then cooled to −20° C. The resultant suspension was vacuum filtered through a 1 cm bed of dry silica in a 150 mL fritted funnel. The silica was washed with 2.5 L of chloroform. The chloroform filtrate was reduced in vacuo to about 1 L, washed in a separatory funnel with 3×1 L volumes of water followed by one 3×1 L volume of brine to remove traces of succinimide, then dried with magnesium sulfate and vacuum filtered. The chloroform was reduced by rotary evaporation at reflux at 1 atmosphere to 250 mL and cooled at −20° C. for 3 days. The resultant crystals were vacuum filtered, washed with 30 mL of chloroform followed by 50 mL of hexanes, then dried in a vacuum oven at room temperature overnight, providing 8.48 g (54%) 2-bromomethylbenzoic acid as a white crystalline power.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:2]=[CH:3][C:4]([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccc2)cc1
Yield: 98 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionate (270 mg), which is the product of Example 75, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and the reaction mixture was treated to give the title compound (250 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]2[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]2)(=[O:36])=[O:35])[C:24]([Cl:43])=[CH:23][N:22]=1>>[Cl:43][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]2[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]2)(=[O:35])=[O:36])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCC(O)C1
Reactant: COCCNC1CCc2ccc(N)c(OC)c2CC1
Product: COCCNC1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCC(O)C4)n3)c(OC)c2CC1
Yield: 7 %

Procedure:
In an analogous manner to Experimental 691, part c, 1-methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and 1-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-benzenesulfonyl]-pyrrolidin-3-ol were combined to yield 1-(2-{5-Chloro-2-[1-methoxy-7-(2-methoxy-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-benzenesulfonyl)-pyrrolidin-3-ol (12.27 mg, 7% yield) as a beige foam. 1H-NMR (CDCl3) δ 9.36 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.59 (m, 1H), 7.46 (s, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.35 (s, 1H), 3.72 (s, 3H), 3.45 (m, 2H), 3.38 (m, 5H), 3.28 (m, 2H), 2.80-2.75 (m, 4H), 2.68-2.45 (m, 2H), 2.13-1.85 (M, 4 h), 1.25 (M, 6 h). LC/MS (ESI+)=617 (M+H).
Reaction SMILES: [C:1]1(=[O:20])[N:5]([C@@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:7]([OH:9])=[O:8])[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.C(OCC)(=O)C>[C:4]1(=[O:15])[N:5]([C@@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:7]([O:9][CH3:21])=[O:8])[C:1](=[O:20])[C:2]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:3]12
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 196 %

Procedure:
A slurry of (S)-2-phthalimido-6-hydroxyhexanoic acid (3.752 g., 13.5 mmol.) and cesium carbonate (2.178 g., 6.7 mmol.) in dimethylformamide (44 ml.) was treated with methyl iodide (3.0 ml., 6.84 g., 48.2 mmol.). After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate and washed successively with water containing a small amount of sodium bisulfite, water, 50% saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give the title product as a colorless oil (3.825 g.). The oil was homogeneous by TLC (1:1-acetone:hexanes) Rf =0.37.