Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[S:10][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:35])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[CH:20][CH:19]=2)=[N:8][CH:7]=1>CO.O1CCCC1.[OH-].[Li+]>[C:29]1([CH3:34])[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[NH:27][C:25](=[O:26])[NH:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[C:9]2[S:10][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:7][N:8]=2)=[O:35])=[CH:23][CH:22]=1
Reactant: COC(=O)CCc1cnc(C2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCCC2c2ncc(CCC(=O)O)s2)cc1
Reaction time: 4 h
Yield: 93.7 %

Procedure:
A solution was prepared of 3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid methyl ester (0.33 g, 0.65 mmol) in methanol (4 mL), tetrahydrofuran (8 mL) and aqueous lithium hydroxide (2M, 4 mL). The solution was stirred for 4 h and partitioned between aqueous hydrochloric acid (1N, 30 mL) and ethyl acetate (100 mL). The aqueous portion was extracted with ethyl acetate (50 mL). The combined organic portions were extracted with brine (20 mL) and the solvent removed in vacuo to give the title compound (0.3 g, 94%). 1HNMR (400 MHz, CD3OD): δ7.60 (d, J=7.3 Hz, 1H), 7.46 (s, 0.3H), 7.39 (d, J=8.5 Hz, 2.7H), 7.29 (d, J=8.5 Hz, 0.6), 7.18 (m, 3H), 6.99 (m, 1.4H), 5.40 (d, J=7.0 Hz, 0.3H), 5.34 (d, J=6.0 Hz, 0.7H) 3.4-3.8 (m, 4H), 3.05 (m, 2H), 2.60 (m, 2H), 2.27 (s, 3H), 1.9-2.2 (m, 4H). MS: Calc'd for C25H26N4O4S: 492.18. Found: (M+1) 492.9.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[C:10]([CH3:11])[C:2]=1[NH2:1]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)O)c(N)c1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(OC)c(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of 2-amino-4-methoxy-3-methyl benzoic acid (3.1 g, 17.1 mmol) in dry DMF (40 ml) was added potassium carbonate (2.4 g, 17.1 mmol) and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (3.1 g, 22 mmol) was added and the mixture was stirred for three hours at room temperature. A 5% aqueous solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (2.75 g).
Reaction SMILES: C(O)(C)(C)C.[SH2:6].[N+:7]([C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[S:18])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].[SH-].[K+:20]>CCOCC>[N+:7]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[S:6])[S-:18])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].[K+:20]
Reactant: S
Reactant: O=[N+]([O-])c1cccc(N=C=S)c1
Agent: [K+]
Agent: [SH-]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cccc(NC(=S)[S-])c1
Reaction time: 2 h

Procedure:
A mixture of 75.0 grams of potassium t-butylate in 500 ml. of t-butyl alcohol is saturated with hydrogen sulfide. With the temperature kept below 35°C. by cooling, a mixture of 120.0 grams of m-nitrophenyl isothiocyanate in 500 ml. of ether is added to the potassium hydrosulfide solution in three portions. After the mixture is stirred an additional 2 hours, the solids are collected by filtration, washed with ether, and dried under vacuum to give 162 grams of potassium m-nitrophenyldithiocarbamate. This salt is added portionwise over about 15 minutes to a stirred ice-cooled mixture of 174 grams of methylene bromide and 65 grams of triethylamine in 600 ml. of dimethylformamide with the reaction temperature at 25°C. to 30°C. After another 5 hours of stirring at room temperature, the mixture is poured into 3.5 liters of ice-water precipitating a light yellow solid. The solids, after drying, are taken up in benzene (ca. 2 liters), filtered free of some insoluble material, and the benzene mixture is saturated with dry hydrogen chloride. The precipitated solids are collected by filtration, washed with benzene, and then stirred vigorously with a water-benzene mixture at 60°C. to 70°C. The benzene layer is separated, washed with water and sodium bicarbonate solution, dried, and concentrated in vacuo to give 102 grams of crude product. The solids are dissolved in 800 ml. of ethanol. The mixture is filtered and diluted with 1200 ml. of ether. Then the mixture is cooled to -35°C. The resulting light yellow solids are collected and vacuum dried to give 84.0 grams of product, melting point 96.0°C. to 97.0°C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13]S(C1C=CC=CC=1)(=O)=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[ClH:23].[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][N:32]=[C:31]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:30]=2[CH:40]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[ClH:23].[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][N:32]=[C:31]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:13][CH2:12][CH2:11][C:10]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[NH:3][C:2]=4[CH3:1])[CH2:36][CH2:35]3)[C:30]=2[CH:40]=1
Reactant: COc1ccc2onc(C3CCNCC3)c2c1
Reactant: Cc1[nH]c2ccccc2c1CCCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COc1ccc2onc(C3CCN(CCCc4c(C)[nH]c5ccccc45)CC3)c2c1

Procedure:
A mixture of 4.0 g of 2-methyl-3-(3-phenylsulfonylpropyl)indole, 3.0 g of 5-methoxy-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, 8.0 g of potassium carbonate and 70 ml of 2-butanone was heated under reflux, with stirring, and refluxed under nitrogen for 16 hours. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. The insoluble material was collected and washed with diluted sodium hydroxide to give a solid. The ethylacetate extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give an additional solid. Treatment of the combined solids with a saturated hydrogen chloride-toluene solution gave the salt. The salt was triturated with acetone and recrystallized from ethanol-ether to give an ethanolate, mp 163°-165° (foaming). Recrystallization of the alcoholate from acetonitrile and subsequent drying of the sample at 100° and ca 1 mm gave 1.60 g (33%) of product, mp 130°-132°.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[CH2:6]1[C:11](=O)N(Br)[C:8](=O)[CH2:7]1>CC1(C)N([O])C(C)(C)CCC1.C(OCC)(=O)C>[CH2:8]([CH2:2][CH:1]=[O:4])[CH2:7][C:6]1[CH:11]=[CH:8][CH:7]=[CH:6][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=CCCCc1ccccc1
Yield: 125.2 %

Procedure:
β-Phenethylalcohol (2.0 g, 16.4 mmol), sodium acetate (2.0 g, 24.6 mmol), TEMPO (26 mg, 0.16 mmol) and ethyl acetate (15 ml) were put in a 50-ml egg plant type flask. The suspension was cooled to less than 10° C. in an ice bath, and thereto was added NBS (3.2 g, 18.0 mmol) divided in two portions. The insoluble materials were filtered off and the filtrate was washed with 5% aqueous sodium bicarbonate solution. The crude product was purified by distillation to give phenethylacetaldehyde (1.67 g, yield 85%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7].[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: COCCNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCNC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 72.2 %

Procedure:
A mixture of methyl 2-(3-(2-methoxyethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.25 mmol) in methanol (4.5 mL) and 1N sodium hydroxide aqueous solution (3.7 mL, 3.7 mmol) was heated to reflux for 1 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=2. The precipitated white solid was collected by filtration and washed with water, dried in vacuo to afford 69 mg of 2-(3-(2-methoxyethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 71.9%. LC-MS(M+1)=383.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10][C:9]2=O)=[CH:4][CH:3]=1.[CH2:18]([C:25]1[CH:29]=[CH:28][NH:27][C:26]=1CO)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:12]([CH:13]([CH3:15])[CH3:14])[C:11]([O:10][CH2:9][C:26]2[NH:27][CH:28]=[CH:29][C:25]=2[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2C(=O)OC(=O)C2C(C)C)cc1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Product: Cc1ccc(NC(C(=O)OCc2[nH]ccc2Cc2ccccc2)C(C)C)cc1

Procedure:
Following the above procedure, 3-(4-methylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with 3-benzylpyrrolylmethyl alcohol to give 3-benzylpyrrolylmethyl 2-(4-methylphenylamino)-3-methylbutanoate.
Reaction SMILES: [C:1]([N:8]1[CH2:25][CH2:24][C@@:15]23[C:16]4[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:1]([N:8]1[CH2:25][CH2:24][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of N-Boc-3-hydroxymorphinan 2 (20 mg, 0.058 mmol) and triethylamine (9 μL, 0.064 mmol) in dry CH2Cl2 (1 mL) was slowly added pivaloyl chloride (8 μL, 0.064 mmol) at 0° C. and the mixture stirred for 1 h. Solvent was removed under reduced pressure. The crude product was purified on a silica gel column chromatography (5:1 n-Hexane/EtOAc) to give a colorless oil (23 mg, 92% yield): 1H NMR (300 MHz, CDCl3) 0.9˜1.7 (m, 29H); 2.34 (d, J=9.9 Hz, 1H); 2.52˜2.73 (m, 2H); 3.09˜3.17 (m, 1H); 3.73˜3.84 (m, 1H); 6.83˜6.87 (m, 1H); 6.95 (s, 1H); 7.09˜7.12 (m, 1H).
Reaction SMILES: [NH2:1][C@@:2]([C:17]1[CH:22]=[C:21]([Br:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])([CH3:16])[C:3]([F:15])([F:14])[C:4]([CH3:13])([O:6][CH2:7][C:8](OCC)=[O:9])[CH3:5].CCCCCCC>C(OCC)(=O)C>[Br:23][C:21]1[C:20]([F:24])=[CH:19][C:18]([F:25])=[C:17]([C@:2]2([CH3:16])[C:3]([F:15])([F:14])[C:4]([CH3:13])([CH3:5])[O:6][CH2:7][C:8](=[O:9])[NH:1]2)[CH:22]=1
Reactant: CCOC(=O)COC(C)(C)C(F)(F)[C@](C)(N)c1cc(Br)c(F)cc1F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)c(F)cc2F)C1(F)F
Yield: 62.6 %

Procedure:
Prepared in an analogous manner as described for intermediate A22A from (R)-ethyl 2-(4-amino-4-(5-bromo-2,4-difluorophenyl)-3,3-difluoro-2-methylpentan-2-yloxy)acetate (intermediate A22B) (16.1 g; 37.4 mmol). After silica gel column chromatography with heptane and ethyl acetate the (R)-5-(5-bromo-2,4-difluorophenyl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (9.0 g, 23.4 mmol, 63% yield) was obtained as an off-white solid. MS (ISP): m/z=384.2 [(M+H)+] and 386.1 [(M+2+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O>[C:10]1([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:3][C:4]=2[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[O:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Nc1ccc(O)cc1C(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OCc2ccccc2)cc1C(=O)c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 144.6 %

Procedure:
To a solution of N-[4-hydroxy-2-(phenylcarbonyl)phenyl]benzamide (4.0 g, 12.6 mmol) in dimethyl formamide (DMF) (15 mL) was added potassium carbonate (K2CO3) (large excess) then benzyl bromide (660 μL, 5.5 mmol). The reaction was stirred overnight. It was added to water (100 mL) then extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (Na2SO4) then concentrated under vacuo to give a solid which was recrystallized with ethyl acetate/hexane to give the title compound (3.24 g, 63% yield, analytical).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].Cl.[C:16]1([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:30]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:26][CH2:25]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4.8 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 6.1 parts of 4-(diphenylmethoxy)piperidine hydrochloride, 7.5 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and water is added. The layers are separated and the 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 1-{3-[4-(diphenylmethoxy)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 149.2° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 24 h
Yield: 85 %

Procedure:
A solution of methyl 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 3) (1.0 g, 2.270 mmol) in methanol (15 mL) at room temperature was treated with aqueous sodium hydroxide solution (2N, 2.27 mL, 4.54 mmol) and the resulting mixture was stirred at this temperature for 24 h. The bulk of MeOH was evaporated in vacuo and the aqueous residue was treated with acetic acid (0.39 mL, 6.81 mmol) giving precipitate which was isolated by filtration and dried under vacuum at 40° C. to afford 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (820 mg, 1.923 mmol, 85% yield) as a yellow solid. LCMS (HpH, 2 min), Rt=0.64 min, MH+=427.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:31][N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCCC[C@H]1c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
To a suspension of NaH (60% in mineral oil, 171 mg, 4.27 mmol) in DMF (4.00 mL) was added Intermediate A (175 mg, 1.07 mmol) and the reaction stirred for 20 min. Intermediate 62b (250 mg, 1.07 mmol) was added in DMF (2.00 mL) and the reaction heated to 60° C. for one hour. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH and product eluted with 2M NH3 in MeOH. The resulting residue was purified by FCC, using 2-10% [2M NH3 in MeOH] in DCM, to give the title compound (287 mg, 71%). LCMS (Method 1): Rt 1.64, m/z 378.2 [MH+].
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.I[C:45]1[C:46]([O:54][CH3:55])=[N:47][N:48]([CH2:50][CH2:51][CH2:52][OH:53])[CH:49]=1>>[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28]([C:45]2[C:46]([O:54][CH3:55])=[N:47][N:48]([CH2:50][CH2:51][CH2:52][OH:53])[CH:49]=2)=[CH:29][CH:30]=1
Reactant: CNC(=O)c1nc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COc1nn(CCCO)cc1I
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cn(CCCO)nc2OC)ccc1N
Yield: 29 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Compound 48D, 500 mg, 2 mmol) and 3-(4-iodo-3-methoxy-pyrazol-1-yl)-propan-1-ol (Compound 48E, 600 mg, 2.18 mmol) to afford 177 mg of the title compound (30%). 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 4.11 (t, J=6.8 Hz, 2H), 3.98 (s, 3H), 3.57 (t, J=6.2 Hz, 2H), 2.93 (s, 3H), 2.05 (t, J=6.4 Hz, 2H). MS (ESI): m/z=306.24 [M+H]+. UPLC: tR=0.75 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:20][CH2:19][C:18]3[N:17]4[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:11][C:10]=3[C:9]2=[O:21])[C:3]=1[CH2:22][OH:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([O:23][CH2:22][C:3]1[C:4]([N:8]2[CH2:20][CH2:19][C:18]3[N:17]4[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:11][C:10]=3[C:9]2=[O:21])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:33])[CH3:32]
Reactant: O=C1c2cc3n(c2CCN1c1nccc(Cl)c1CO)CCCC3
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a mixture of 244a (900 mg, 2.7 mmol) and triethylamine (810 mg, 8.1 mmol) in dichloromethane (30 mL) was added acetyl chloride (630 mg, 8.1 mmol) dropwise. The reaction mixture was stirred at 30° C. for 1 h. It was then concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with dichloromethane to afford 244b as white solid (900 mg, 90%). MS-ESI: [M+H]+ 374.2
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[C:8]([CH3:14])[CH:7]=2)[CH2:5][CH2:4]1.[Cl:15][C:16]1[N:17]=[C:18](Cl)[C:19]2[NH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN1C(=O)CCC1.O>[Cl:15][C:16]1[N:17]=[C:18]([O:13][C:9]2[C:8]([CH3:14])=[CH:7][C:6]([CH:3]3[CH2:5][CH2:4]3)=[CH:11][C:10]=2[CH3:12])[C:19]2[NH:24][CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: Cc1cc(C2CC2)cc(C)c1O
Reactant: Clc1nc(Cl)c2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
To a stirred suspension of NaH (25 mg, 0.64 mmol) in dry NMP (1.5 mL) was added 4-cyclopropyl-2,6-dimethylphenol (103 mg, 0.64 mmol) and the resolution mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (120 mg, 0.64 mmol) in dry NMP (1.7 mL) and heated at 90° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1-2:1), to give the product as a light yellow solid (20.2 mg, 8%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:11])=[N:6][CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([N:6]1[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c([N+](=O)[O-])c(O)ccn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a solution of 3-nitro-pyridine-2,4-diol (5.0 g, 32.3 mmol) in DMF (50 mL) at 0° C. was added NaH (2.6 g, 64.0 mmol 60% in mineral oil). After stirring at 0° C. for 15 min, benzyl bromide (6.03 g, 35.2 mmol) was added and the reaction was stirred at 55° C. for 17 h. The mixture was cooled to room temperature, poured into ice water, and filtered to remove insoluble material. The filtrate was acidified with 1 N HCl, extracted with CH2Cl2, dried with MgSO4, and concentrated. The product was washed with EtOH to give 1-benzyl-4-hydroxy-3-nitro-1H-pyridine-2-one (3.30 g, 42% yield). 1H-NMR (DMSO): δ 7.90 (d, 1H, J=7.6 Hz), 7.27–7.38 (m, 5H), 6.12 (d, 1H, J=7.6 Hz), 5.08 (s, 2H). MS: calculated for C12H10N2O4+H 247.1; found: 247.2.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:9](=[O:11])[N:10]=1)=[NH:4].[NH2:27][CH2:28][C@H:29]([OH:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[OH:39][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:12]=[C:8]3[S:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:1])[CH3:26])=[N:10][C:9]3=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)S1

Procedure:
The title compound was prepared from N,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) and 4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.50-3.30 (m, 9 H), 3.70-3.90 (m, 7 H), 4.90 (brs, 1 H), 6.66 (d, J=6.8 Hz, 1 H), 6.74 (d, J=6.8 Hz, 1 H), 7.01 (d, J=8.8 Hz, 2 H), 7.41 (d, J=8.8 Hz, 2 H), 7.47 (s, 1 H); MS (ES) m/z: 270.0 ((M+2H)2+, 100%); 539.1 (MH+, 10%); HRMS Calcd. for C27H35N6O4S (MH+): 539.2441. Found: 539.2422.