Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:20])([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH:9]([OH:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)(Cc1ccc(Cl)cc1)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C(C)(Cc1ccc(Cl)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methyl-2-butanone (1.6 g, 4.6 mmol) in methanol (50 mL) was added sodium borohydride (0.26 g, 6.8 mmol). After stirring at room temperature for 10 min, the reaction was quenched by addition of saturated aqueous ammonium chloride (25 mL). The precipitate was filtered off and washed with ethyl acetate (25 mL). The organic layer of the filtrate was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluted with 5% ethyl acetate in hexane to afford the title compound as two separate diastereomers. Faster eluting diastereomer (Diastereomer α) 1H NMR (400 MHz, CD3OD): δ 7.63 (s, 1H), 7.42-7.18 (m, 3H), 7.05 (d, 2H), 6.80 (d, 2H), 3.92 (q, 1H), 3.19 (d, 1H), 2.86 (d, 1H), 1.13 (s, 3H), 1.02 (d, 3H). Slower eluting diastereomer (Diastereomer β) 1H NMR (400 MHz, CD3OD): 7.40-7.18 (m, 4H), 7.04 (d, 2H), 6.64 (d, 2H), 4.12 (q, 1H), 3.04 (ABq, 2H), 1.17 (s, 3H), 0.84 (d, 3H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[C:15]([O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:14]=1)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][N:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][CH2:10][CH2:9][NH:7][CH3:6])=[O:30])=[CH:14][C:15]=1[O:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH3:22]
Reactant: CN(C)Cc1ccc(C(=O)NCCN(C)C(=O)OC(C)(C)C)cc1Oc1cccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCNC(=O)c1ccc(CN(C)C)c(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a solution of {2-[4-dimethylaminomethyl-3-(pyridin-3-yloxy)-benzoylamino]-ethyl}-methyl-carbamic acid tert-butylester (250 mg, 0.58 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (1 mL). The reaction was allowed to stir at rt for 16 h and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL), washed with 1 M NaOH (15 mL), dried (Na2SO4), and concentrated under reduced pressure. FCC purification (MeOH/CH2Cl2) provided the desired product (0.13 g, 68%) as a yellow oil. MS (ESI): m/z found, 329.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][CH:37]=[C:38]([CH:41]=2)[CH:39]=[O:40])O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:20]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:2]([C:34]2[CH:35]=[N:36][CH:37]=[C:38]([CH:41]=2)[CH:39]=[O:40])=[N:3]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (2 g, 5.7 mmol) in 1,4-dioxane (40 mL) and H2O (8 mL) under nitrogen was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1.48 g, 6.30 mmol), and potassium carbonate (2.39 g, 17.0 mmol). Upon completion of addition, the reaction mixture was degassed with nitrogen for 15 min and then (1,1′-bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (0.46 mg, 0.050 mmol) was added. The reaction mixture was again degassed for 10 min with nitrogen. At the conclusion of this period, the reaction mixture was stirred at 90° C. for 16 h, then allowed to cool to room temperature and quenched by the addition of water. The reaction mixture was transferred to a separation funnel and the aqueous layer was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography using 2.7% MeOH in DCM as eluent to afford 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinaldehyde (1.8 g, 100% yield) as an off-white solid. LCMS Method Y: retention time 1.99 min; [M+1]=418.4.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH3:16][C:17]([OH:20])([CH3:19])[CH3:18].[NH:21]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:22]([C:35](O)=[O:36])[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:21]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:22]([C:35]([O:20][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:36])[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 10 h
Yield: 83.9 %

Procedure:
To an ice-cold CH2Cl2 (60 mL) solution of DCC (9.78 g, 47.34 mmol), t-BuOH (17.54 g, 0.24 mol) and DMAP (0.29 g, 2.37 mmol); a CH2Cl2 (40 mL) solution of 2 (16.00 g, 47.34 mmol) was added slowly over 20 min. Then reaction mixture was allowed to stir 1 h at 0° C. and 10 h at 20° C. Precipitated urea was then filtered off and the filtrate evaporated in vacuo. The residue was taken up in CH2Cl2, and if necessary, filtered free of any further precipitated urea. The CH2Cl2 solution was washed twice with 10% citric acid solution and with saturated NaHCO3 solution, and then dried over Na2SO4. The residue obtained after evaporation of CH2Cl2 was purified by column chromatography to obtain the product as a clear viscous oil (15.67 g, 84% yield). 1H NMR (300 MHz, CDCl3) δ7.26 (5H), 5.53 (1H), 5.45 (1H), 5.02 (2H), 4.26-4.18 (1H), 3.59-3.46 (2H), 1.38 (9H), 1.37 (9H); 13C NMR (75 MHz, CDCl3) δ 169.9, 156.8, 155.8, 136.6, 128.7, 128.3, 82.8, 80.1, 66.9, 54.7, 43.3, 28.5, 28.1; ESI-LRMS m/z 395.2 (M+H)+, 417.2 (M+Na)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]([CH2:11][OH:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[H-].[Na+].O>O1CCCC1>[CH3:9][CH:8]([CH3:10])[CH2:7][C@@H:6]1[NH:5][C:3](=[O:4])[CH2:2][O:12][CH2:11]1
Reactant: CC(C)C[C@@H](CO)NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H]1COCC(=O)N1
Reaction time: 14 h

Procedure:
(S)-2-Chloro-N-[1-(hydroxymethyl)-3-methylbutyl]acetamide, 26.34 g (0.136 mol), is dissolved in 450 ml of tetrahydrofuran, the solution is cooled to 0°-5° C. and 7.8 g (0.195 mol) of 60% sodium hydride in mineral oil dispersion is slowly added. The mixture is allowed to reach room temperature and is stirred for 14 hours. Water, 10 ml, is added, the solvents evaporated in vacuo and the residue suspended in 250 ml of chloroform and washed with 100 ml of water and then a saturated aqueous solution of sodium chloride, 2×200 ml. The chloroform layer is separated, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by chromatography using silica gel and eluting with dichloromethane methanol (95:5) to give (S)-5-(2-methylpropyl)-3-morpholinone, 5.1 g, mp 69°-70°; [α]D25 -13.7° (c 1.11, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[NH2:37][CH2:38][CH2:39][C:40]#[N:41]>>[C:40]([CH2:39][CH2:38][NH:37][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:41]
Reactant: N#CCCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCC#N)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-aminopropionitrile.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:17]12([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C:30](Cl)=[O:31])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>ClCCl>[C:17]12([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C:30]([S:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)=[O:31])[CH2:18][CH:19]3[CH2:25][CH:23]([CH2:22][CH:21]([CH2:20]3)[CH2:26]1)[CH2:24]2
Reactant: O=C(O)c1ccc(S)cc1
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
In a round bottom flask, there are introduced 1.7 g (11 mmoles) of 4-mercaptobenzoic acid and 20 ml of pyridine. There is then slowly added a solution of 3.4 g (11.17 mmoles) of 3-(1-adamantyl)-4-methoxybenzoic acid chloride in 50 ml of dichloromethane. The reaction mixture is o stirred at ambient temperature for 8 hours, evaporated to dryness, taken up in 100 ml of water and acidified to pH 5 with 1N HCl. The solid is filtered, washed with water and dried at 60° C. under a vacuum, then recrystallized in dioxan. 3.3 g (75% yield) of 4-[3-(1-adamantyl)-4-methoxybenzoylthio] benzoic acid having a melting point of 264° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@H:29]([OH:44])[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1>>[OH:43][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][C@@H:29]([OH:44])[CH2:28][NH:27][CH:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:12]=[CH:13][C:8]([CH:7]=[C:6]4[S:5][C:4]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)=[N:3][C:2]4=[O:1])=[CH:9][CH:10]=3)[CH2:19][CH2:18]2)=[CH:37][C:36]=1[NH:38][S:39]([CH3:42])(=[O:41])=[O:40]
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CNC2CCN(c3ccc(C=C4SC(N5CCCCC5)=NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 14) according to the procedure of Example 1 as a yellowish solid; mp >95° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H), 2.55-2.90 (m, 6 H), 2.92 (s, 3 H), 3.60 (br s, 2 H), 3.70-3.95 (m, 6 H), 6.61 (dd, J=8.8, 2.9 Hz, 1 H), 6.75-6.80 (m, 2 H), 7.02 (d, J=9.0 Hz, 2 H), 7.45 (d, J=9.0 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 315.6 ((M+2H)2+, 100%); 630.1 (MH+, 100%); HRMS Calcd. for C30H40N5O6S2 (MH+): 630.2420. Found: 630.2397.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2Br)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Brc1ccccc1SC1CCNCC1
Yield: 99 %

Procedure:
To a stirred solution of 2-bromobenzenethiol (1.0 g, 0.00529 mole) in DMF (10 mL) was added cesium carbonate (2.063 g, 0.0063 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.478 g, 0.00529 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was washed with hexane to afford 1.93 g (98%) of 4-(2-bromo-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 372.06 (M+1)+, 92.78%. A solution of 4-(2-bromo-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (1.93 g, 0.0052 mole) in dioxane.HCl (3 mL), was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 1.38 g (99%) of 4-(2-bromo-phenylsulfanyl)-piperidine hydrochloride. 1H NMR (DMSO-d6): δ 9.1-8.9 (bs, 1H), 7.7-7.64 (d, 1H), 7.56-7.52 (d, 1H), 7.46-7.36 (t, 1H), 7.24-7.16 (t, 1H), 3.7-3.6 (m, 1H), 3.34-3.2 (bd, 3H), 3.1-2.94 (q, 2H), 2.16-2.04 (d, 2H), 1.84-1.66 (q, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[C:6]([NH2:21])=[N:7][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[N:9][C:10]=1[NH2:11].Br[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:13]=2)=[N:7][C:6]=1[NH2:21]
Reactant: COC(=O)Nc1c(N)nc(-c2n[nH]c3ncccc23)nc1N
Reactant: BrCC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Nc1c(N)nc(-c2nn(CC3CCCCC3)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
330 mg (1.1 mmol) of the compound of Example 1A and 212 mg (1.2 mmol) of bromomethylcyclohexane were initially charged in 5 ml of dimethylformamide, 389 mg (1.2 mmol) of cesium carbonate were added and the resulting mixture was stirred at RT overnight. 0.5 ml of 1N hydrochloric acid was added, and the entire solution was separated by HPLC (Method 5). The appropriate fractions were freed from volatile components on a rotary evaporator, and the residue was dried under high vacuum. This gave 60 mg (19% of theory) of the target compound.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:23]=[CH:22][O:21][CH:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:21]1[CH:22]=[CH:23][C:19]([C:2]#[C:1][N:3]2[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]3[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]2=3)=[CH:20]1
Reactant: Brc1ccoc1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccoc2)CCN(C)C1
Temperature: 80 °C
Yield: 5.1 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (180 mg, 0.81 mmol), 3-bromofuran (100 mg, 0.68 mmol), dichlorobis(triphenylphosphine)palladium (II) (14 mg, 0.02 mmol) and TBAF.3H2O (642 mg, 2.0 mmol) was heated at 80° C. for 5 min by microwave. After completion of reaction (monitored by TLC), the mixture was poured into water (10 mL) and extracted with EtOAc (3×10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to obtain product, which was purified by reverse phase chromatography to obtain 10 mg of 5-furan-3-ylethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.70 (s, 1H), 7.50-7.4 (m, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 6.55 (s, 1H), 3.68 (s, 2H), 3.0-2.90 (m, 4H), 2.60 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: O=Cc1ccco1
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C1CCC(N2Cc3c(NCc4ccco4)cccc3C2=O)C(=O)N1
Reaction time: 24 h
Yield: 29.5 %

Procedure:
To a stirred suspension of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.52 g, 2.0 mmol) in methanol (50 ml) was added furan-2-carbaldehyde (0.200 g, 2.05 mmol). The mixture was heated to reflux for 4 hours. The solvent was evaporated in vacuo and the residue was dissolved in acetic acid (20 ml). Sodium triacetoxyborohydride (0.450 g, 2.05 mmol) was added to the reaction mixture. The reaction mixture was stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml), washed with H2O (3×100 ml), saturated aqueous NaHCO3 (2×100 ml), brine (1×100 ml), and dried over MgSO4. The solvent was evaporated in vacuo and the residue was partially purified by chromatography (100% ethyl acetate) to give an off-white solid which was recrystallized from ethanol to give 0.20 g of product as a white solid: mp 248-250° C.; 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 7.57 (s, 1H), 7.27 (t, J=7.6 Hz, 1H), 6.96 (d, J=7.3 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.36 (d, J=11.2 Hz, 2H), 6.22 (t, J=5.4 Hz, 1H), 5.12 (dd, J=4.9 and 13.1 Hz, 1H), 4.37 (d, J=5.5 Hz, 2H), 4.27 (d, J=17.2 Hz, 1H), 4.14 (d, J=17.2 Hz, 1H) 3.00-2.86 (m, 1H), 2.65-2.59 (m, 1H), 2.37-2.23 (m, 1H), 2.08-1.99 (m, 1H); 3C NMR (DMSO-d6) δ 172.83, 171.16, 168.70, 152.82, 143.06, 142.00, 132.09, 129.02, 126.76, 112.35, 110.63, 110.33, 107.08, 51.50, 45.73, 31.20, 22.75; Anal. Calcd. For C18H17N3O4: C, 63.71; H, 5.05; N, 12.38. Found: C, 63.41; H, 5.03; N, 11.98.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=O)[O:9][CH:10](O)[C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.S(O)(O)(=O)=O.[NH2:19][NH2:20].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:9])[NH:19][N:20]=[CH:10][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: O=C1OC(O)c2cc(Cl)nc(Cl)c21
Reactant: NN
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc2cc(Cl)nc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4,6-dichloro-1-hydroxy-1H-furo[3,4-c]pyridin-3-one (9.37 g) stirring in water (100 ml) was added hydrazine sulfate (10.58 ml) and sodium acetate (13.56 g). The reaction mixture was heated at reflux and stirred for 2 h. The reaction mixture was cooled to RT, diluted with water (150 ml) and extracted with EtOAc (2×75 ml). The combined organic layers were washed with saturated Na2CO3 solution and dried over Na2SO4. Evaporation to dryness gave the desired product as brown solid.
Reaction SMILES: [N:1]1[C:8]([F:9])=[N:7][C:5](F)=[N:4][C:2]=1[F:3].[NH2:10][C:11]1[C:12]([OH:45])=[C:13]([N:21]=[N:22][C:23]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:24][NH:25][C:26]2[CH:31]=[C:30]([S:32]([OH:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=2[C:36]([OH:38])=[O:37])[CH:14]=[C:15]([S:17]([OH:20])(=[O:19])=[O:18])[CH:16]=1.[OH-].[Na+].Cl>O>[F:9][C:8]1[N:1]=[C:2]([F:3])[N:4]=[C:5]([NH:10][C:11]2[C:12]([OH:45])=[C:13]([N:21]=[N:22][C:23]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[N:24][NH:25][C:26]3[CH:31]=[C:30]([S:32]([OH:35])(=[O:33])=[O:34])[CH:29]=[CH:28][C:27]=3[C:36]([OH:38])=[O:37])[CH:14]=[C:15]([S:17]([OH:20])(=[O:19])=[O:18])[CH:16]=2)[N:7]=1
Reactant: Nc1cc(S(=O)(=O)O)cc(N=NC(=NNc2cc(S(=O)(=O)O)ccc2C(=O)O)c2ccccc2)c1O
Reactant: Fc1nc(F)nc(F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)O)cc1NN=C(N=Nc1cc(S(=O)(=O)O)cc(Nc2nc(F)nc(F)n2)c1O)c1ccccc1
Reaction time: 0.25 h

Procedure:
9.65 parts of cyanuric fluoride are added to a neutral solution of 35.80 parts of the copper complex of 5-amino-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]-4-hydroxybenzenesulfonic acid in 350 parts of water at 0 to 2° C. in the course of 10 minutes. During the addition the pH is kept at 5.8 to 6 with a 15% sodium hydroxide solution. After the addition the mixture is stirred for about 15 minutes, the pH is brought to 3.5 to 3.8 with 32% hydrochloric acid and the mixture is stirred again for about 15 minutes. The pH is then brought to about 5.8 to 6 with a 15% sodium hydroxide solution. A solution of 5-[4,6-difluoro-1,3,5-triazin-2-ylamino]-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]-4-hydroxybenzenesulfonic acid is obtained.
Reaction SMILES: [O:1]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]2)[CH2:2]1.[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][CH2:2][C:3]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1)[CH3:14]
Reactant: CCN
Reactant: CCOC(=O)N1CCC2(CO2)C1
Product: CCNCC1(O)CCN(C(=O)OCC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8 g (46.7 mmol) of ethyl 5-aza-1-oxaspiro[2,4]heptane-5-carboxylate are added dropwise to 50 ml of ethylamine solution (50% in water) and the mixture is stirred overnight at room temperature. It is concentrated and the residue is distilled.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([Br:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:6].[OH-].[Na+].Cl>CO>[Br:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:7]([N:5]([CH3:6])[CH2:4][C:3]([OH:20])=[O:2])=[O:8]
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(Br)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(=O)O)C(=O)c1cccc2c(Br)cccc12
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
N-[(5-Bromo-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (3.7 g, 11.0 mmoles, described in Example 2) was suspended in methanol (50 ml). A solution of 1N aqueous NaOH (13.2 ml) was added to the suspension. The mixture was stirred at 20°-22° C. for 1.5 hr. The mixture was neutralized with aqueous HCl and concentrated under reduced pressure to remove the methanol. The residual solution was made acidic with aqueous HCl and extracted with ethyl acetate. The extract was dried (MgSO4), filtered and evaporated to dryness. The residue was crystallized from ethanol-water to give 3.25 g of the title compound; mp 205° C.; NMR(DMSO-d6) δ2.75 and 3.10 (2s, 3H), 2.75 and 3.10 (2s, 3H), 3.75 and 4.25 (2s, 2H), 7.3-8.3 (m, 6H); IR (Nujol *) 1745 with inflection at 1720, 1580 cm-1 ; UVλmax (EtOH) 322 nm (ε680), 316 (1,000), 299 (6,510), 289 (9,055), 279 (7,150) 226 (63,080); Anal Calcd: C, 52.19% H, 3.76% N, 4.35%; Found: C, 52.09% H, 38.4% N, 4.48%.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([C:14]([O:16]C)=[O:15])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(C(=O)OC)cnc3n2CC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2nc3cc(C(=O)O)cnc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
To a solution of methyl 3-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (260 mg, 0.71 mmol) in THF/MeOH (1:1, 6 ml) was added 1 N NaOH (3 ml, 3 mmol). The reaction mixture was stirred at room temperature for 3 h, and concentrated in vacuo. The residue was dissolved in H2O (10 ml), and acidified by adding 1 N HCl solution to pH5. The solid was collected (230 mg), and the filtrate was extracted with EtOAc (2×50 ml). The extracts were dried over Na2SO4 and concentrated in vacuo to afford an additional crop of product (20 mg). The desired acid was produced in quantitative yield.