Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CNc1ccc(C(CC)=NOCc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of the product of step 3 (2.2 g, 5.39 mmoles) in THF (10 ml), a solution of lithium hydroxide (0.45 g, 10.77 mmoles) in water (10 mL) was added and the reaction mixture was stirred at 25° C. for 3 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and neutralized to pH 6 with 1N HCl. Solid seperated was filtered, washed with water and dried over CaCl2 under vacuum to give 1.64 g (82%) of title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]([CH3:40])[C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:3]=[C:2]([C:28]4[CH:27]=[N:26][C:25]([N:24]([CH3:40])[CH3:23])=[N:30][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cnc(N(C)C)nc3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester (140 mg, 0.561 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N,N-dimethylpyrimidin-2-amine. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.8 (s, 2H), 7.6-7.77 (m, 3H), 7.4 (d, 1H), 7.3 (s, 1H), 7.1 (d, 1H), 6.97 (d, 1H), 4.77 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.3 (s, 6H), 3.1 (m, 4H), 3.0 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:24])([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=3[F:19])[C:10]2=[O:23])[C:5](=[O:25])[NH:4][C:3]1=[O:26].Cl.N[C:29]1(C)C(=O)N(CCC)C(=O)N[C:30]1=O>>[CH3:24][C:6]1([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=3[F:19])[C:10]2=[O:23])[C:7](=[O:8])[N:2]([CH2:1][CH2:29][CH3:30])[C:3](=[O:26])[NH:4][C:5]1=[O:25]
Reactant: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Reactant: CCCN1C(=O)NC(=O)C(C)(N)C1=O
Agent: Cl
Product: CCCN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O

Procedure:
Compound 19b was synthesized in the same manner as described for 19a from 5-amino-5-methyl-1-propylbarbituric acid hydrochloride (0.38 g, 1.50 mmol). The crude product was recrystallized from EtOH (70%) to give 5-methyl-1-propyl-5-(tetrafluorophthalimido)-barbituric acid (19b) as white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(Cl)Cl.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O>[CH3:33][S:34]([O:27][CH2:26][CH2:25][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:28])[CH3:29])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:22][CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])(=[O:36])=[O:35]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)CCO)c3)ncnc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A mixture of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) was cooled at 0° C. To this mixture, TEA (50 μL, 0.0004 mol) was added. The reaction was stirred for 15 minutes. Methanesulfonyl chloride (23 μL, 0.00030 mol) was added and the resulting mixture was stirred for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentane-1,5-diyl dimethanesulfonate (57 mg, 80%) as an oil. MS(ES): 574 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:29]=[CH:28][S:27][CH:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:29]=[CH:28][S:27][CH:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Brc1ccsc1
Product: OC1(c2ccsc2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 81 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromothiophene, the title compound was formed in 81% yield as an off-white solid, mp 273°-277° C. (dec). free base: 1H NMR (CDCl3, 250 MHz) 7.17 (m, 7H), 6.94 (m, 4H), 4.26 (s, 1H), 3.46 (s, 1H), 2.84 (m, 2H), 2.71 (m, 2H), 2.60 (d, J=1.4 Hz, 2H), 2.12 (m, 2H), 1.83 (m, 2H) MS (CI, CH4) m/z 388 (M+1,100), 416 (M+29,20), 370 (51), 304 (10), 196 (12) hydrochloride salt:
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:6]([OH:16])[C:5]([N+:17]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pd]>[NH2:17][C:5]1[C:6]([OH:16])=[C:7]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:9])=[O:10])[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O
Yield: 9 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 6-chloro-N-cyclopropylmethyl-2-hydroxy-3-nitrobenzenesulfonamide (0.1 g, 3.2 mmol) was reduced with hydrogen and 10% Pd/C (0.1 g) to form the desired product (0.08 g, 89%). LC-MS m/z 277 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.Br[C:27]1[CH:31]=[CH:30][S:29][C:28]=1[C:32]#[N:33].O>COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+].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>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([C:27]4[CH:31]=[CH:30][S:29][C:28]=4[C:32]#[N:33])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: N#Cc1sccc1Br
Reactant: Cc1ccn2c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cnc2c1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2c(-c3cccc(-c4ccsc4C#N)c3)cnc2c1
Yield: 57.1 %

Procedure:
A mixture of 7-methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]imidazo[1,2-α]pyridine (350 mg, 1.0 mmol) and 3-bromo-2-cyanothiophene (200 mg, 1.0 mmol) in 1,2-dimethoxyethane (10 ml) and caesium carbonate (5 ml of a 2M solution) was degassed for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.1 mmol) was then added and the mixture heated at reflux for 20 hours, poured into water (50 ml) and extracted with ethyl acetate (2×25 ml). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. Purification by flash chromatography eluting with 3% methanol in dichloromethane gave the title compound as a colourless oil (180 mg, 57%). Oxalate salt, white powder, m.p. 193-195° C. (Found C, 62.07; H, 3.66; N, 10.19. C19H13N3S.C2H2O4 requires C, 62.21; H, 3.73; N, 10.36). 1H NMR (360 MHz, d6-DMSO) δH 2.42 (3H, s), 6.91-6.93 (1H, m), 7.53 (1H, s), 7.68-7.82 (6H, m), 7.89 (1H, s), 8.01 (1H, s), 8.18 (1H, d, J 5), 8.63 (1H, d, J 7); m/z (ES+) 316 (M++H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:16](Cl)=[O:17]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:16]([NH:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[O:17]
Reactant: NCCCn1cncn1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1cncn1)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
A mixture of about 3.78 g of 1H-1,2,4-triazole-1-propanamine and about 33 ml of approximately 1N sodium hydroxide in about 100 ml of methylene chloride was stirred. An about 6.9 g portion of 3,4-dichlorobenzoyl chloride was added, the mixture was stirred about 6 hours, then allowed to stand overnight. An about 10 ml portion of approximately 1N sodium hydroxide and about 100 ml of methylene chloride were added and the mixture was shaken, then allowed to separate. The organic layer was washed with two about 40 ml portions of water, dried, filtered and evaporated to a solid which was crystallized from ethyl acetate, giving about 5.0 g of the desired product as off-white crystals, mp 128°-130° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=2)[CH:9]=[N:8][CH:7]=1.CCN(CC)CC.[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=1)=O.[BH3-]C#N.[Na+]>CO>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][NH:3][CH2:28][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=3)=[CH:7][N:8]=[CH:9]2)=[CH:13][C:14]=1[F:20])#[N:17]
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1F
Reactant: O=Cc1ccccc1NC(=O)c1cccc(O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cn2cncc2CCNCc2ccccc2NC(=O)c2cccc(O)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride (Step F) (0.64 g, 2.03 mmol) in MeOH (15 mL) was added NEt3 dropwise to pH=4.5. To this solution was added N-(2-formyl-phenyl)-3-hydroxy-benzamide (0.64 g, 2.64 mmol) and NaCNBH3 (0.255 g, 4.06 mmol), and the reaction was stirred 18 h at 25° C. The MeOH was removed in vacuo, and the residue was partitioned with EtOAc and saturated NaHCO3. The organic layer was separated and washed 3× with 10% HCl. The acidic layers were combined, made basic with Na2CO3, then extracted 3× with EtOAc. These layers were combined, washed with brine and dried (MgSO4). Filtration and concentration in vacuo gave the crude product which was purified by prep HPLC to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:14]([CH3:16])([CH3:15])[C:12](=[O:13])[N:11]([CH2:17][C:18]#[CH:19])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:20]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([N:8]1[C:14]([CH3:15])([CH3:16])[C:12](=[O:13])[N:11]([CH2:17][C:18]#[C:19][I:20])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C#CCN1C(=O)N(Cc2ccccc2)C(C)(C)C1=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: CC1(C)C(=O)N(CC#CI)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.3 %

Procedure:
To a stirred solution of 1-benzyl-3-propargyl-5,5-dimethylhydantoin (1.2 g, 4.6 mmole) in acetone (50 mL) at room temperature was added finely ground silver nitrate (0.15 g. 0.8 mmole), followed by N-iodosuccinimide (1.16 g, 5.2 mmole). The reaction mixture was stirred at room temperature for 5 hr. The reaction mixture was then passed through Celite by suction filtration and washed with acetone. The titrate was concentrated on a rotary evaporator and diluted with ethyl acetate. The solution was washed with water and brine and dried over sodium sulfate. The solvent was evaporated on a rotary evaporator to give 1.5 g of 1-benzyl-3-(3-iodo-2-propynyl)-5,5-dimethylhydantoin as a solid, mp=109°-112° C. An NMR spectrum also showed the desired structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](O)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[CH2:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(O)c1ccc(Cl)nc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C(=O)OCC)c1ccc(Cl)nc1OC
Yield: 179.8 %

Procedure:
A mixture of ethyl 2-(6-chloro-2-methoxypyridin-3-yl)-2-hydroxypropanoate (220 g, 847 mmol) and TsOH·H2O (80.5 g, 423 mmol) in dry toluene (1.5 L) was heated at reflux azeotropically with a Dean-Stark trap for 5 h. All of reaction solutions were combined together for work up. After being cooled, the combined reaction mixtures were washed with 10% Na2CO3 aq., and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to afford ethyl 2-(6-chloro-2-methoxypyridin-3-yl)acrylate (368 g 90%) as a black oil, which was used for next step without any further purifications.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from the product of Example 2 (140 mg), collidine (0.061 mL), and DMAP (8.1 mg) in 6.7 mL anhydrous DMF is cooled to 0° C. Methanesulfonyl chloride (0.12 mL) is added dropwise. The reaction is stirred at room temperature for approx. 2-3 hrs. Morpholine (0.34 mL) is added. The product is precipitated by addition of H2O. The crude product is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 70.1 mg (42%) of the title compound as a white solid.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][O:24][CH2:25][CH:26]1[NH:31][CH2:30][CH2:29][N:28]([C:32]2[N:37]=[CH:36][C:35]([C:38](OC)=[O:39])=[CH:34][N:33]=2)[CH2:27]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:38]([C:35]3[CH:34]=[N:33][C:32]([N:28]4[CH2:29][CH2:30][NH:31][CH:26]([CH2:25][O:24][CH3:23])[CH2:27]4)=[N:37][CH:36]=3)=[O:39])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COCC1CN(c2ncc(C(=O)OC)cn2)CCN1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COCC1CN(c2ncc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CCN1
Temperature: 60 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
Trimethylaluminium (2M in toluene, 1.596 mL, 3.19 mmol) was added dropwise to a solution of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (314 mg, 1.27 mmol) and methyl 2-(3-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carboxylate (338 mg, 1.27 mmol) in toluene (6.35 mL) at 25° C. The resulting mixture was stirred at 60° C. for 18 h under nitrogen. The reaction mixture was added to methanol (100 mL) and treated with HCl (2N aqueous solution, until pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford the crude product as a yellow dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (348 mg, 57%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2cnnn2)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (Example H15) according to the general procedure K. Obtained as a light red solid (129 mg).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12](=[CH2:14])=[N-:13]>C(O)(=O)C>[N+:12](=[CH:14][C:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N-:13]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Product: [N-]=[N+]=CC(=O)CCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of hydrocinnamoyl chloride (10.00 grams; 100 mL dry diethyl ether) was carefully added to freshly prepared etherial diazomethane (85.6 grams Diazald; 100 mL dry ethyl ether) at 0° C. The reaction was held at 0° C. until outgassing subsided (15 minutes), then raised to room temperature (15 minutes). Acetic acid (5.0 mL) was added and the reaction partitioned (pH4 pthalate buffer and methyl tert-butyl ether). The organic was washed with water, dried over MgSO4 and filtered to provide, upon evaporation, an oil containing the title compound. The crude product was used with no further purification or delay.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)=[O:28])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C@H:9]([C:19]([O:21]C)=[O:20])[CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:13])=[O:7]>CO>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)=[O:28])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:13])=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc2c1cnn2C1CCCCO1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
An aqueous solution of sodium hydroxide (1 M, 190 UL, 0.19 mmol) was added to a solution of N-[2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (108 mg, ˜0.169 mmol) in methanol (1 mL). The solution was allowed to stir at room temperature for 2 days, then it was concentrated and held under high vacuum for 1 h to give N-[2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (100 mg, 97%) as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(OC(C)(C)C)=O>CN(C=O)C>[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([N:24]3[CH2:23][CH2:22][CH:21]([NH2:20])[CH2:26][CH2:25]3)=[O:7])=[CH:4][CH:3]=2)=[O:11])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: CN(C)C=O
Product: NC1CCN(C(=O)c2ccc(C(=O)N3CCC(N)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of terephthaloyl chloride (1.02 g, 5.0 mmol) in DMF (10 mL) under an inert atmosphere of argon is treated dropwise with a solution of 4-(N-Boc-amino)piperidine (2.00 g, 10.0 mmol) over 20 minutes. The reaction mixture is allowed to stir at room temperature for 40 minutes and then TEA (2.09 mL, 15.0 mmol) is added dropwise. A white suspension forms and stirring continues for 2 hours. The resulting mixture is washed with saturated NaHCO3 solution (50 mL) and water (100 mL). The resulting mixture is filtered under vacuum using phase separating paper to afford a white solid. The solid is dried under vacuum at 45° C. to yield the required product. [M+H]+ 531
Reaction SMILES: Cl.[OH:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[CH2:13]([C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:24][N:23]([C:4](=[O:6])[C@H:3]([OH:2])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)[C@H](O)c1ccccc1
Yield: 26.7 %

Procedure:
Proceeding as in Example 1, but substituting (R)-2-hydroxy-2-phenylacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 40, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-((R)-2-hydroxy-2-phenylacetyl)pyrrolidine-2-carboxamide (8.4 mg, 26.7%). 1H-NMR (400 MHz, DMSO-D6): σ 10.03 (s, 1H), 7.56 (d, 2H), 7.27 (m, 11H), 6.97 (m, 5H), 5.20 (s, 1H), 4.44 (t, 1H), 2.86 (t, 2H), 2.71 (s, 1H), 2.45 (d, 2H), 1.80 (m, 2H). MS (EI) for C32H29FN2O4: 525.4 (MH+).