Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.[OH-].[K+]>C1C=CC=CC=1.C(O)C>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:6]2[CH:7]=[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: CCOC(=O)CCCNc1ccc(OC)c(-c2ccccc2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(CCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1-c1ccccc1
Yield: 74.9 %

Procedure:
8.0 g of ethyl 4-(6-methoxybiphenyl-3-yl)aminobutyrate and, 3.3 g of ethyldiisopropylamine in 50 ml of benzene are reacted, analogously to Example 47b), with 4.6 g of p-chlorobenzoyl chloride. The reaction product is dissolved in 50 ml of benzene and, after the addition thereto of a solution of 2.3 g of potassium hydroxide in 20 ml of ethanol, is then stirred for 8 hours at room temperature. After distilling off the solvent, the residue is dissolved in water; the resulting solution is acidified with dilute hydrochloric acid and extracted with diethyl ether. The residue (remaining after evaporating off the ether) is recrystallized from ethyl acetate/petrol ether (1:1) to obtain 8.1 g (73.5% of theory) of 4-[p-chloro-N-(6-methoxybiphenyl-3-yl)-benzamido]butyric acid, MP 114° to 116°.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1([CH2:23][CH3:24])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3>C(O)C.[OH-].[Na+]>[CH2:23]([C:5]1([CH2:4][C:3]([OH:25])=[O:2])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:14][CH:13]=3)[CH3:24]
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1ccc(OC(F)(F)F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC1(CC(=O)O)OCCc2c1[nH]c1ccc(OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
A mixture of 1-ethyl-1,3,4,9-tetrahydro-6-(trifluoromethoxy)pyrano[3,4-b]indole-1-acetic acid methyl ester (6.2 g, 17.4 mmol) in ethanol (80 mL) and 2.5N NaOH (24 mL) was stirred at ambient temperature under nitrogen for 3 hours. The ethanol was removed in vacuo and the residue was diluted with H2O (70 mL) and washed with ether. The aqueous phase was acidified (to pH3) with 2N-HCl and extracted with Et2O. The extract was washed with brine and dried (Na2SO4). Removal of the solvent afforded the crude product (5.2 g, amber oil). Crystallization from Et2O-hexane gave 3.43 g of the pure title compound (mp 148° C., white solid). A second crop was obtained from the mother liquor (0.54 g, mp 148° C., light brown solid). The combined yield was 67%.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10](S)[CH3:11].[F:13][C:14]1[C:27]([NH:28][C:29]([CH:31]2[CH2:35][CH2:34]C[N:32]2C(OCC2C=CC=CC=2)=O)=[O:30])=[CH:26][C:17]2[N:18]([CH2:23][C:24]#[CH:25])[C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1.[OH-].[Na+].O>C(Cl)Cl.O>[F:13][C:14]1[C:27]([NH:28][C:29]([CH:31]2[NH:32][CH2:10][CH:11]3[CH:35]2[CH2:34]3)=[O:30])=[CH:26][C:17]2[N:18]([CH2:23][C:24]#[CH:25])[C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1
Reactant: CCS
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)C3CCCN3C(=O)OCc3ccccc3)cc21
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCN1C(=O)COc2cc(F)c(NC(=O)C3NCC4CC43)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.8 %

Procedure:
To a solution of boron trifluoride etherate (1.57 gm, 10.8 mmol) and ethanethiol (2.31 mL, 1.94 gm, 32.32 mmol) under N2, at room temperature was added dropwise a solution of the compound of Step F, Example 3, (500.0 mg) in CH2Cl2 (1 mL). The resultant clear solution was stirred at room temperature for 48 hours and the reaction was scrubbed with a bleach/50% NaOH/H2O-20%. 30 mL of water was added dropwise at room temperature followed by CH2Cl2 (30 mL). The aqueous layer was separated and basified to pH 10 using 50% NaOH. Additional 30 mL of CH2Cl2 was added and the organic layer was separated, dried (MgSO4) and evaporated to dryness to give the title compound of Step G as a white solid (200 mg), 57%; m.p. 196°-198° C.; IR (nujol, cm-1): 1676.0 (C=O), 3357.7 and 3301.7 (NH); 1H NMR δ: 0.08-0.09 (m,1H), 0.71-0.77 (m,1H), 1.41-1.43 (m,1H), 2.01-2.08 (m,1H), 2.11-2.17 (broad s, 1H), 2.31-2.32 (m,1H), 3.02 (s,2H), 3.72 (s,1H), 4.61 (s,2H), 4.75-4.81 (dd,2H), 6.79-6.81 (d,1H), 8.44-8.46 (d,1H), 9.85 (broad s,1H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=O)[CH:25]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:6]([O:13][C:14]1[C:19]([C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:18][CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH2:1])[CH:25]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1cccc(-c2cccc(C(=O)c3ccccn3)c2)c1OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1)c1ccccn1
Reaction time: 1 h
Yield: 16 %

Procedure:
A solution of methyltriphenylphosphoniumbromide (1.4 g, 3.9 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred under nitrogen on an ice bath and 2.5 M n-butyllithium in hexanes (1.5 mL, 3.75 mmol) was slowly added. After 20 min. the cold bath was removed and stirring was continued at room temperature for 1 hr. The reaction mixture was cooled on an ice bath and a solution of 11 (0.82 g, 1.95 mmol) in tetrahydrofuran (15 mL) was added at such a rate that the temperature did not exceed 5° C. Stirring was continued overnight at room temperature. The reaction mixture was poured on saturated ammonium chloride (120 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×80 mL), dried over sodium sulfate and stripped. The residue was purified by chromatography on silica (50 g) with 5% ethyl acetate in heptane (3 L) to produce pure 12 (0.13 g, 16%).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH2:15][CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:6][O:5]C(=O)[NH:3]1.[OH-].[K+].O.C([C@H]([C@@H](C([O-])=O)O)O)([O-])=O>O1CCCC1.CO.C(O)C.C(Cl)Cl>[NH2:3][C@:2]([CH3:1])([CH2:8][CH2:9][C:10]1[N:11]([CH2:15][CH3:16])[CH:12]=[CH:13][CH:14]=1)[CH2:6][OH:5]
Reactant: CCn1cccc1CC[C@]1(C)COC(=O)N1
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCn1cccc1CC[C@@](C)(N)CO
Reaction time: 4 h
Yield: 64.8 %

Procedure:
(4R)-4-Methyl-4-[2-(1-ethylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (4.90 g, 22.0 mmol) obtained in Reference example 3 (3d) was dissolved in a mixture of tetrahydrofuran (80 mL) and methanol (40 mL) and a 5.5 N aqueous potassium hydroxide solution (40 mL) was added thereto, followed by heating under reflux of the mixture for 4 days. After cooling, water and methylene chloride were added to the reaction mixture to separate it. The thus obtained organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was dissolved in 200 mL of ethanol. After a solution of D-(−)-tartrate (1.59 g, 10.5 mmol) in ethanol (20 mL) was added thereto and the mixture was left to stand for 4 hours, the precipitated crude crystal was recrystallized from a mixture of ethanol (100 mL) and water (10 mL). The obtained crystal was recrystallized again from a mixture of ethanol (50 mL) and water (5 mL) to obtain the title compound (2.80 g, yield: 37%) as a colourless plate-like crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH:7]([CH3:17])[CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[F:24][C:25]([F:31])([F:30])[S:26](O)(=[O:28])=[O:27]>ClCCl.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[CH:7]([CH3:17])[CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(CSc1ccc(O)cc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(CSc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon and at −78° C., to a solution of the compound prepared in Example 1(2) (1.50 g) in dichioromethane (10 ml), pyridine (1.1 3 ml) and anhydrous trifluoromethanesulfonic acid (1.13 ml) were added dropwise. The mixture solution was stirred for 2 hours at room temperature. A saturated aqueous solution of sodium bicarbonate (20 ml) was added to the reaction mixture and it was vigorously stirred for 1 hour at room temperature. The reaction mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (hexane:ethyl acetate=19: 1) to give the title compound (2.05 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[CH:11]([C:12]([O:14]CC)=[O:13])[S:10][CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1.[OH-].[K+].O>CO>[CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[S:10][CH2:9][C:8](=[O:17])[C:7]=2[CH:18]=1
Reactant: CCOC(=O)C1SCC(=O)c2cc(OC)c(OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)C(C(=O)O)SCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
In methanol (20 ml) was suspended ethyl 6,7-di-methoxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (6 g) followed by addition of 2N-KOH (15 ml) and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6,7-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (4.4 g, yield 82%). Recrystallization from methanol gave colorless prisms. m.p. 212°-213° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[F:11].C1([O:18][C:19](=O)[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)C=CC=CC=1.C(#N)C>C(N(CC)CC)C>[NH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:19]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)=[O:18])=[CH:5][C:4]=1[F:11]
Reactant: CC(C)(C)c1ccc(CNC(=O)Oc2ccccc2)cc1
Reactant: NCc1ccc(N)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccc(CNC(=O)NCc2ccc(N)c(F)c2)cc1

Procedure:
To the 50 ml of round bottom flask were put 4-amino-3-fluorobenzylamine hydrochloride (0.46 g, 3.28 mmol) and 4-t-butylbenzylcarbamic acid phenyl ester (1.1 eq, 1.02 g). And to this mixture was poured 20 ml acetonitrile and added triethylamine (excess, 0.5 ml) and refluxed 12 hours. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed with 1N HCl solution. And the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (n-hexane/ethyl acetate=1/1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[NH2:12][NH2:13]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:13][N:12]=[C:8]2[CH3:9]
Reactant: CC(=O)c1cc(Br)ccc1F
Reactant: NN
Product: Cc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To 1-(5-Bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol) was added anhydrous hydrazine (240 mL, 7.65 mol). The reaction mixture was heated under reflux for 10 hours. The reaction mixture was allowed to cool to room temperature and was stirred for 16 hours. The reaction mixture was added to ice (1.4 L). The reaction mixture was stirred for 30 minutes. The reaction mixture was filtered and the white solid product was washed with water. The white solid was dried in a vacuum oven to afford the desired 5-bromo-3-methyl-1H-indazole 104 (86.1 g, 0.408 mol) which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)([O-:3])=[O:2].CO.C(NCC)C>C(=O)=O>[N+:1]([C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:19])=[O:20])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc(NC[C@H]2CCCOC2)c([N+](=O)[O-])c1
Agent: O=C=O
Solvent: CCNCC
Solvent: CO
Product: NS(=O)(=O)c1ccc(NC[C@@H]2CCCOC2)c([N+](=O)[O-])c1

Procedure:
The racemic mixture of EXAMPLE 11A was resolved by chiral SFC on an AD column (21 mm i.d.×250 mm in length) using a gradient of 10-30% 0.1% diethylamine methanol in CO2 over 15 minutes (oven temperature: 40° C.; flow rate: 40 mL/minute) to provide the title compound.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]1[CH:33]=[CH:32][N:31]2[N:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:30]2[N:29]=1.O.NN.C1COCC1>CO>[NH2:3][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]1[CH:33]=[CH:32][N:31]2[N:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:30]2[N:29]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCCN3C(=O)c4ccccc4C3=O)nc12
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCCN)nc12
Temperature: 25 °C
Yield: 71.7 %

Procedure:
(R)-ethyl 5-(2-(2-(3-(1,3-dioxoisoindolin-2-yl)prop oxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 0.359 mmol) and hydrazine monohydrate (115 mg, 3.59 mmol) were combined in MeOH (1 mL) and THF (1 mL) in a sealed vessel and heated at 60° C. for 20 minutes. After cooling to ambient temperature, the reaction was concentrated, followed by addition of NaOH (1 N, 2 mL). The mixture was extracted with DCM, and the combined organic extracts were dried (Na2SO4), filtered and concentrated to afford (R)-ethyl 5-(2-(2-(3-aminoprop oxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (110 mg, 72% yield). MS (apci) m/z=428.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:14]=[C:15]([CH3:17])[N:16]=[C:4]2[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][C:15]1[N:16]=[C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][N:5]2[N:14]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1nc2nc(Cl)c(-c3ccccc3)cn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Temperature: 90 °C

Procedure:
To a mixture of 6.90 g 5-chloro-2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine and 4.65 g 4-formylphenylboronic acid in 100 mL 1,2-dimethoxyethane were added 55 mL of a 10% w/w sodium carbonate solution and 1.03 g dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II). The resulting mixture was heated to 90° C. under an inert gas atmosphere for 18 h. The work up was performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers were dried over sodium sulphate and the solvent was evaporated. The residue was purified by chromatography on silica gel (dichloromethane/methanol) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=CCCc1ccc(Br)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Brc1ccc(CCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.03 g (4.82 mmol) 3-(4-bromo-phenyl)-propionaldehyde and 0.41 mL (4.82 mmol) pyrrolidine in 50 mL MeOH is adjusted to pH 4-5 with glacial acetic acid. Then 400 mg (6.05 mmol) NaBH3CN are added batchwise and the reaction is stirred for 3 days at RT. The reaction solution is diluted with 30 mL water and the aqueous phase is extracted with 50 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 9:1:0.1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S-:28].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([S:28][CH3:27])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 25 °C
Yield: 65 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (56 mg, 0.13 mmol) in dry DMF (1 mL) at 60° C. was added sodium methanethiolate (9.9 mg, 0.14 mmol). The reaction was heated to reflux for 30 min and then cooled to room temperature. The reaction was quenched with 1M aq. NaOH and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a yellow oil. The oil was purified by flash chromatography (silica gel, 0-33% EtOAc in hexanes) to give 34 mg of the desired product as a colorless oil. MS (ESI) 403 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH:9]([CH3:15])[C:10](OCC)=O)=[N:8][C:4]=2[CH:3]=1.[NH2:18][C:19]1[CH:38]=[CH:37][C:22]([C:23]([NH:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[O:24])=[CH:21][C:20]=1[NH:39][CH3:40]>CN1CCCN(C)C1=O>[OH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH:9]([C:10]3[N:39]([CH3:40])[C:20]4[CH:21]=[C:22]([C:23]([NH:25][CH2:26][CH2:27][O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[O:35][CH3:36])=[O:24])[CH:37]=[CH:38][C:19]=4[N:18]=3)[CH3:15])=[N:8][C:4]=2[CH:3]=1
Reactant: CNc1cc(C(=O)NCCOc2ccccc2OC)ccc1N
Reactant: CCOC(=O)C(C)c1nc2cc(O)ccc2[nH]1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccccc1OCCNC(=O)c1ccc2nc(C(C)c3nc4cc(O)ccc4[nH]3)n(C)c2c1
Temperature: 170 °C
Yield: 13.1 %

Procedure:
A mixture comprising ethyl 2-(5-hydroxy-1H-benzoimidazol-2-yl)propionate (148 mg, 0.63 mmol), 4-amino-N-[2-(2-methoxyphenoxy)ethyl]-3-methylaminobenzamide (200 mg, 0.63 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (0.5 mL) was stirred at room temperature until homogeneous, degassed under vacuum and concentrated by heating at 170° C. for 2 hours under a stream of N2. The residue was cooled to room temperature and rinsed with an excess of ethyl ether. The resulting amorphous material was taken up in 50% aqueous acetonitrile and purified by preparative reverse phase HPLC (2-50% CH3CN/H2O) to provide 2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-N-[2-(2-methoxyphenoxy)ethyl]-3-methyl-3H-benzoimidazole-5-carboxamide (40 mg, 13% yield) as a light pink solid; MS (BioIon) C27H27N5O4 m/e calc 485.59; found 486.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][C@@H:19]([CH2:23][OH:24])[NH:20][CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][C@@H:19]([CH2:23][OH:24])[N:20]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN[C@H](CO)C3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)N(C)C)[C@H](CO)C3)cc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of Example 260H (150 mg, 0.352 mmol) in N,N-dimethylformamide (1.8 mL) was added N-ethyl-N-isopropylpropan-2-amine (227 mg, 1.759 mmol) and 2-chloro-N,N-dimethylacetamide (39.9 μL, 0.387 mmol). The mixture was stirred for 3 days at room temperature and for 2 hours at 70° C., and partitioned between water and ethyl acetate (three times). The extracts were dried over sodium sulfate, filtered, and concentrated, and the residue was purified by flash chromatography on silica gel, eluting with a gradient of 0-8% methanol/dichloromethane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.18 (d, J=5.0 Hz, 1H), 7.31-7.16 (m, 3H), 7.02 (d, J=5.0 Hz, 1H), 6.46 (s, 1H), 6.18 (d, J=1.8 Hz, 1H), 4.61 (t, J=5.3 Hz, 1H), 3.74 (s, 3H), 3.60-3.27 (m, 6H), 3.33 (s, 3H), 3.02 (s, 3H), 2.93 (dd, J=11.1, 5.7 Hz, 1H), 2.81 (s, 3H), 2.48-2.32 (m, 2H); MS (ESI+) m/z 439.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:19])[C:12](=[CH2:18])[CH2:13][C:14](OC)=[O:15]>CCOC(C)=O>[CH3:9][O:10][C:11]([CH:12]1[CH2:13][C:14](=[O:15])[N:1]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:18]1)=[O:19]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: Nc1ccc(O)cc1
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Temperature: 110 °C

Procedure:
A mixture of 4-amino-phenol (3 g, 0.027 mol) and 2-methylene-succinic acid dimethyl ester (4.35 g, 0.027 mol) was heated to 110° C. for 16 h. The dark brown glass was dissolved in EtOAc and purified by silica gel chromatography (20% EtOAc/hexane to EtOAc) to give an orange oil. MS (ESI pos. ion) m/z: 236.2 (M+H). Calc'd Exact Mass for C12H13NO4: 235.24.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Temperature: 60 °C
Yield: 87.8 %

Procedure:
To stirred solution of 2,5-dichloro-3-nitrobenzoic acid (3.2 g, 13.67 mmol) in DMF (30 mL) was added sodium carbonate (4.3 g, 40.56 mmol) and methyl iodide (9.7 g, 68.30 mmol). The reaction mixture was heated at 60° C. for 18 h. On completion, water was added to the reaction mixture, and the product was extracted using DCM. The combined organic layers were dried and concentrated under reduced pressure to give methyl 2,5-dichloro-3-nitrobenzoate (3 g, 90%).