Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23]C(OC(C)(C)C)=O)[CH:17]=1)[CH2:5][P:6]([CH:11]([NH2:15])[CH:12]([CH3:14])[CH3:13])([O:8]CC)=[O:7].CCN(C(C)C)C(C)C.[C:41]1([S:47](Cl)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C[Si](Br)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:23][CH2:22][C:18]1[CH:17]=[C:16]([CH:4]([CH2:5][P:6]([CH:11]([NH:15][S:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:49])=[O:48])[CH:12]([CH3:13])[CH3:14])([OH:8])=[O:7])[C:3]([OH:2])=[O:31])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOP(=O)(CC(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1)C(N)C(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccccc1)P(=O)(O)CC(C(=O)O)c1cccc(CN)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 2-(3-(t-butoxycarbonylamino)methylphenyl)-3-((1-amino-2-methylpropyl)(ethoxy)phosphinoyl)propanoic acid methyl ester (344 mg, 0.75 mmol) in methylene chloride (10 mL) was added DIEA (394 μL, 2.25 mmol) followed by DMAP (3.4 mg (cat.)). The reaction mixture was cooled to 0° C. and a solution of benzenesulfonylchloride (200 mg, 1.13 mmol) in methylene chloride was added dropwise over 15 minutes. The reaction mixture was stirred at 0° C. for 30 minutes and allowed to warm to ambient temperature overnight. The reaction was diluted with methylene chloride and washed with 2 N aq NaHSO4, water, brine and dried over sodium sulfate. Evaporation gave a crude residue (425 mg) that was dissolved in 2.5 mL of methylene chloride and cooled to 0° C. under N2. TMSBr (1 mL) was added dropwise and the reaction was stirred at ambient temperature overnight, quenched with MeOH and evaporated. The resulting residue was dissolved in 5 mL of MeOH/H2O (1:1), neutralized with 0.25 M aq LiOH and 300 mg of LiOH and 10 mL of H2O. The reaction mixture was stirred at ambient temperature overnight. The solvents were evaporated and purification by preparative HPLC yielded 150 mg of 2-(3-(amino)methylphenyl)-3-((1-(phenylsulfonyl)amino-2-methylpropyl)(hydroxy)-phosphinoyl)propanoic acid, NMR (DMSO-d6) 0.5-0.8 (m, 6), 1.8 (m, 1), 1.92 (m, 1), 2.35 (m, 1) 3.25 (m, 1), 3.82 (m, 1), 4.0 (s, 2), 7.2 (dd, 1), 7.25-7.4 (m, 3), 7.4-7.6 (m, 3), 7.8 (m, 3), 8.18 (s, 3) ppm.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:6]=2[N:5]=1.[CH3:18]O>>[F:17][C:3]([F:2])([F:16])[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:18])=[O:14])=[CH:12][C:6]=2[N:5]=1
Reactant: CO
Reactant: O=C(O)c1ccc2[nH]c(C(F)(F)F)nc2c1
Agent: Cl
Product: COC(=O)c1ccc2[nH]c(C(F)(F)F)nc2c1

Procedure:
Gaseous hydrogen chloride is passed through a solution of 59.7 g (0.241 mol) of 14a in 1,000 ml of methanol for 2 hours, simultaneously boiling under reflux. The methanol is then removed by distillation, and the residue is dissolved in ethyl acetate/water and the pH is adjusted to 7 with 2N solution hydroxide solution. The ethyl acetate phase is separated off, the aqueous phase is extracted twice with ethyl acetate, and the organic phase is washed with sodium chloride solution, dried over Na2SO4 and evaporated.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:17][C:16]1[CH:18]=[CH:19][C:13]([C:12]([F:11])([F:20])[F:21])=[CH:14][CH:15]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (white solid, mp 199-200° C.). MS(ES+) m/z 278 ([M+1]+, 100).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:28])[CH:5]([CH:17]([OH:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][S:2]([C:3]1[C:4](=[O:28])[CH:5]([CH:17]([OH:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:37]
Reactant: CCCCCC(O)C=CC1C=C(SC)C(=O)C1C(O)CCCCCC(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC(O)C=CC1C=C(S(C)=O)C(=O)C1C(O)CCCCCC(=O)OC
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a solution of 35 mg of 2-methylthio-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone obtained in Example 20 dissolved in 5 ml of dichloromethane was added 17 mg of 3-chloroperbenzoic acid, and the mixture was stirred for 1 hour. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. An organic layer was added, and the mixture was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel chromatography to give 7.3 mg (yield 21%) of 2-methylsulfinyl-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16](=[N:18][OH:19])[NH2:17])=[N:13][N:12]=2)[CH2:7][CH2:6]1.[CH3:25][C:26]1([CH3:36])[O:30][C@H:29]([CH2:31][C:32](F)=O)[C:28](=[O:35])[O:27]1>>[Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:17]=[C:32]([CH2:31][C@H:29]4[O:30][C:26]([CH3:36])([CH3:25])[O:27][C:28]4=[O:35])[O:19][N:18]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)F)O1
Reactant: NC(=NO)c1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Product: CC1(C)OC(=O)[C@@H](Cc2nc(-c3nnc(N4CCC(Oc5cc(F)ccc5Br)CC4)s3)no2)O1

Procedure:
The title compound was prepared in a similar manner as described for Example 13, step 2 from 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-N′-hydroxy-1,3,4-thiadiazole-2-carboximidamide and [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetyl fluoride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([NH:18][C:19](=O)[CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:19]([CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[N:18][C:6]=2[CH:5]=1)=[O:27]
Reactant: COC(=O)c1ccc(NCC2CCCCC2)c(NC(=O)Cc2cccs2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)nc(Cc1cccs1)n2CC1CCCCC1
Yield: 71.3 %

Procedure:
20.0 g 4-(Cyclohexylmethyl-amino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester were dissolved in 65 ml dioxane and reacted with 33 ml of 4M hydrochloric acid in dioxane at rt for 4 h. The reaction was concentrated and the residue purified by chromatography (silica, ethyl acetate/heptane) to yield 13.6 g (71%) of 1-Cyclohexylmethyl-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16](=[N:21][OH:22])[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(CCCCOCc2ccccc2)CC1
Agent: Cl
Product: ON=C1CCN(CCCCOCc2ccccc2)CC1

Procedure:
1-(4-Benzyloxybutyl)-4-piperidone oxime is prepared from 1-(4-benzyloxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]2[NH:12][CH:9]([CH2:10][CH:11]=1)[CH2:8][CH2:7]2)=[O:4].[C:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](F)=[CH:17][CH:16]=1)#[N:14]>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]2[N:12]([C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[CH:9]([CH2:10][CH:11]=1)[CH2:8][CH2:7]2)=[O:4]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: COC(=O)C1=CCC2CCC1N2
Solvent: c1ccncc1
Product: COC(=O)C1=CCC2CCC1N2c1ccc(C#N)c2ccccc12
Yield: 5.8 %

Procedure:
8-Azabicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl ester (225 mg, 1.35 mmol, Davies H. M. L. et al., J. Org. Chem. 1991, 56, 5696-5700), 1-cyano-4-fluoronaphthalene (230 mg, 1.35 mmol) and pyridine (1.0 mL) were heated to 110° C. for 2 days and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate/n-heptane 1:4, 5× eluted) to afford the title compound (25 mg, 6%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>[Pd]>[CH3:1][O:2][C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(/C=C/CO)CCOCC1
Agent: [Pd]
Product: COC1(CCCO)CCOCC1

Procedure:
The desired compound is prepared by catalytic hydrogenolysis of 4-methoxy-4-(3-hydroxy-trans-prop-1-enyl) tetrahydropyran, prepared as in Example 1, steps 1-4, using palladium on calcium carbonate poisoned with lead according to the method of U.S. Pat. No. 5,268,379, Example 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:21][OH:22])=[C:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:21]=[O:22])=[C:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1cccc(-c2c(CO)ccc3ccc(OC)cc23)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cccc(-c2c(C=O)ccc3ccc(OC)cc23)c1
Yield: 92.1 %

Procedure:
7-Methoxy-1-(3-methoxyphenyl)-2-naphthalenemethanol (1.75 g) was oxidized using the reagent prepared as in Example 136 from oxalyl chloride (0.62 mL) and dimethylsulfoxide (0.9 mL) in dichloromethane (14 mL). The usual work up furnished 1.6 g of 7-methoxy-1-(3-methoxyphenyl)-2-naphthalenecarboxaldehyde.
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=O)=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.CN(C=O)C>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:3])(=[O:16])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
A solution of 31.4 ml (430 mmol) of thionyl chloride and 0.2 ml (2.58 mmol) of DMF was quickly added to 10 g (43 mmol) of 4-hydroxybenzenesulfonic acid sodium salt under N2 atmosphere. The resulting mixture is stirred at 65° C. for 6 h. At the end of this time, the mobile, nearly homogenous reaction mixture is poured on ice with vigorous stirring. An oily lower layer is produced and which is dissolved in 100 ml of CH2Cl2. The aqueous layer is extracted with CH2Cl2 and the combined organic solution is dried over MgSO4 and concentrated under reduced pressure to give 8.19 g of 4-hydroxybenzenesulfonyl chloride; NMR (CDCl3): 5.3 (br s, 1H), 7.01 (d, 2H, J=9.08 Hz), 7.94 (d, 2H, J=9.08 Hz).
Reaction SMILES: [ClH:1].[CH3:2][C@:3]([NH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=O.CSC.B>C1COCC1>[ClH:1].[ClH:1].[CH3:2][C@:3]([NH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][N:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: C[C@@](N)(C(=O)N1CCOCC1)c1ccccc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@](N)(CN1CCOCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 156.8 %

Procedure:
Under an argon atmosphere 412 mg of (1S)-1-methyl-2-morpholin-4-yl-2-oxo-1-phenylethylamine hydrochloride (1.522 mmol) were dissolved in 30 mL of dry THF. A 2 M solution of borane dimethylsulfide (4.4 mL, 5.78 mmol) was added dropwise at 0° C. and the mixture stirred for 10 minutes at 0° C. and then allowed to reach room temperature (gas evolution). After 4 hours the reaction was quenched with methanol (added very carefully) and diluted with methanol when effervescence ceased. THF was removed under vacuo and the methanolic solution was heated at 60° C. for 30 minutes. The solvent was at last completely removed recovering 330 mg of the amine that was subsequently dissolved in 15 mL of dioxane and treated with 1.35 mL of HCl 4 N in dioxane. After 1 hour the solvent was evaporated and the product was triturated with diethylether to yield 350 mg of the expected salt.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](B2OCC(C)(C)CO2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].Br[C:48]1[S:49][CH:50]=[C:51]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:52]=1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([C:48]2[S:49][CH:50]=[C:51]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:52]=2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(B2OCC(C)(C)CO2)cc1C)C(=O)OC(C)(C)C
Product: CCOC(=O)c1csc(-c2ccc(N(CC(=O)NCCN(CC)C(=O)OC(C)(C)C)CC(=O)N(C)N3Cc4ccccc4C3)c(C)c2)n1
Yield: 51.8 %

Procedure:
Using the compound (510 mg, 0.802 mmol) of Example 295, step A and ethyl 2-bromothiazole-4-carboxylate (227 mg, 0.962 mmol), and according to the method of Example 295, step B, the title compound (282 mg, yield 52%) was obtained as a brown oil.
Reaction SMILES: BrCC1C=CC=C([C:9]2([C:12]([C:14]3([C:17]4[CH:18]=[C:19](CBr)[CH:20]=[CH:21][CH:22]=4)[CH2:16]C3)=[O:13])[CH2:11][CH2:10]2)C=1.[C-]#[N:26].[Na+]>CN(C)C=O>[CH:9]1([C:12]([C:14]2[CH:16]=[C:20]([CH2:21][C:22]#[N:26])[CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:10][CH2:11]1
Reactant: O=C(C1(c2cccc(CBr)c2)CC1)C1(c2cccc(CBr)c2)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cccc(C(=O)C2CC2)c1
Reaction time: 2 h

Procedure:
α-Bromo-m-tolylcyclopropyl ketone (10 g) in dry dimethylformamide (20 ml) was added dropwise during 1 hour to a stirred suspension of sodium cyanide (1.96 g) in dry dimethylformamide (40 ml). The mixture was cooled to 10° during the addition and for a further hour, then left to stand at 20° for a further 2 hours and poured onto ice (140 g). The mixture was extracted with ethyl acetate (3× 60 ml) and the extracts were combined, washed with water, dried over magnesium sulphate, filtered and evaporated to give a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:20]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[CH:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:20]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[CH:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(O)nc1
Reactant: CNc1cc(-c2cccnc2Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CNc1cc(-c2cccnc2Oc2ccc(N)cn2)ccn1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
In a microwave vial, 5-aminopyridin-2-ol (125 mg, 1.14 mmol) was dissolved in DMSO (0.910 mL, 0.228 mmol) and cesium carbonate (445 mg, 1.37 mmol) was added. The vial was capped with a septum and the reaction was stirred at RT for 25 minutes until a paste was formed. Then 4-(2-chloropyridin-3-yl)-N-methylpyridin-2-amine (50 mg, 0.23 mmol) was added and the vial was sealed and heated to 180° C. in Personal Chemistry Microwave for 15 min. The mixture was extracted with EtOAc, organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography on silica gel using 60:40 DCM:(90:10:1 DCM:MeOH:NH4OH to flush out top spots, then 50:50 DCM:(90:10:1 DCM:MeOH:NH4OH) to collect the product. Green solid, 4-(2-(5-aminopyridin-2-yloxy)pyridin-3-yl)-N-methylpyridin-2-amine was obtained. MS m/z=294 [M+1]+. Calcd for C16H15N5O: 293.13.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH3:12])[C:5]=1[CH2:13][OH:14])[CH3:2]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH2:11]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=1[CH:13]=[O:14])[CH3:12]
Reactant: CCOc1cccc(OCC)c1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCOc1cccc(OCC)c1C=O
Temperature: 50 °C

Procedure:
A solution of commercially available (2,6-diethoxyphenyl)methanol (500 mg; 2.47 mmol) in anh. CHCl3 (10 ml) was treated with MnO2 (3.342 g; 34.60 mmol), and the resulting mixture was heated to 50° C., under nitrogen, for 20 h. After cooling to rt, the resulting reaction mixture was filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 2,6-diethoxybenzaldehyde as a colorless solid. LC-MS (conditions D): tR=0.89 min.; [M+H]+: 194.99 g/mol.
Reaction SMILES: O[N:2]=[C:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:4]1[CH2:15][C:16]([O:18]CC)=[O:17].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30](O)=[O:31]>>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30]([NH:2][C@H:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][C@H:4]1[CH2:15][C:16]([OH:18])=[O:17])=[O:31]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)CC1CN(c2ccccc2)C(=O)C1=NO
Product: O=C(O)C[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1cc2ccccc2[nH]1

Procedure:
The aminopyrrolidinone of Example 63 is coupled with indole-2-carboxylic acid according to the procedure described in Example 4 and the resulting ester is saponified to give the title homologated acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([OH:22])[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.[OH-].[Na+:24].C1COCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]([C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)=[O:22])[C:11]=1[C:9]([O-:10])=[O:8].[Na+:24]
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)cccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)nc(C(=O)c2cccc(Cl)c2C(=O)[O-])n1

Procedure:
(Table G, cpd. no. 58) 1.24 g of 7-chloro-3-hydroxy-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide, 154 mg NaOH, 25 ml THF and 25 ml water are mixed until a yellow homogenous solution is achieved. The solvents are stripped on a rotovaporator and then on a Kugelrohr at 100° C. to produce the title compound as a yellow solid, m.p. 276°-278° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8]([CH3:17])([C:9]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=O)[CH:7]([CH3:18])[C:6]2=[CH:19][CH:20]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:17][C:8]1([CH2:9][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=[C:6]2[CH:7]1[CH3:18]
Reactant: COc1ccc2c(c1)C(C)(C(=O)N1CCCCC1)C2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(CN1CCCCC1)C2C

Procedure:
A solution of the 1,2-dimethyl compound obtained in Step 1. above (43.8 g) in anhydrous THF (640 ml) is added dropwise to a suspension of LAH (7.6 g) in anhydrous THF (200 ml). The reaction mixture is heated to reflux for 45 minutes, cooled and quenched with water, aqueous NaOH (15%), and water. The reaction mixture is filtered, evaporated in vacuo and chromatographed (silica gel: ethyl acetate/hexane) and the major fractions combined, and evaporated yielding the desired product as an oil which is identified by NMR. The oil is dissolved in methanolic hydrochloric acid, the methanolic solution evaporated and the residue recrystallized (acetonitrile/ether), M.P.=179°-181° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCc1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1ccccc1O
Yield: 88.6 %

Procedure:
A mixture of 4.64 g (14.1 mmol) of N-(tert-butoxycarbonyl)-3-[2-(benzyloxy)phenyl]propylamine, 1.0 g. of 5% palladium-on-carbon catalyst and 95 ml of ethanol was hydrogenated by shaking in a Parr apparatus using an initial pressure of 40 psi of hydrogen for 24 hours until hydrogen uptake was completed. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on a silica gel column which was eluted with a 5 to 20% gradient of ethyl acetate in hexane to give 3.14 g (88.7%) of the product as colorless crystals, mp 75°-77° C.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[N:14][C:13]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[N:21][C:12]2=3)[CH2:5][CH2:4]1.[CH3:24][O:25][C:26]1[C:27]2[CH2:37][CH2:36][C:35](=[O:38])[NH:34][C:28]=2[N:29]=[C:30]([CH:32]=O)[N:31]=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[ClH:1].[CH3:24][O:25][C:26]1[N:31]=[C:30]([CH2:32][NH:2][CH:3]2[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][N:11]3[C:16](=[O:17])[CH:15]=[N:14][C:13]4[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[N:21][C:12]3=4)[CH2:7][CH2:8]2)[NH:29][C:28]2=[N:34][C:35](=[O:38])[CH2:36][CH2:37][C:27]=12
Reactant: COc1nc(C=O)nc2c1CCC(=O)N2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: COC1=C2CCC(=O)N=C2NC(CNC2CCN(CCn3c(=O)cnc4ccc(OC)nc43)CC2)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[2-(4-amino-1-piperidinyl)ethyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one hydrochloride (0.105 g, 0.309 mmol) in 1:1 MeOH/DCM (16 mL) was added 4-(methyloxy)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2-carbaldehyde (0.074 g, 0.309 mmol), NaHCO3 (0.13 g, 1.55 mmol), and excess Na2SO4. The solution was stirred at ambient temperature for 16 h followed by the addition of NaBH(OAc)3 (0.196 g, 0.927 mmol). The resulting solution was stirred for an additional 2 h, then concentrated onto silica gel under vacuum and the crude residue was purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the free base of the desired product as a yellowish oily film (0.114 g, 75%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:29][C:30]([NH2:32])=[O:31].CO>C(Cl)Cl.C(OCC)C>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: NC(=O)CBr
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CC(N)=O)C3)cc1OCC2

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with bromo acetamide. The crude product was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) then trituration in diethyl ether to give 192 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.46 (1H, d, J=8.28 Hz), 7.84 (1H, s), 7.61 (1H, s), 7.07 (1H, dd, J=8.32, 1.84 Hz), 6.95 (1H, d, J=1.79 Hz), 6.89 (1H, s), 5.99-5.90 (1H, m), 5.44 (1H, s), 4.48-4.45 (2H, m), 4.43-4.40 (2H, m), 3.86-3.78 (2H, m), 3.73-3.63 (1H, m), 3.38-3.31 (2H, m), 3.20 (2H, s), 1.56 (6H, d, J=6.64 Hz). LCMS: RT=5.45 min, M+H+=408