Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[C:20](=[C:28]([C:32]([OH:34])=O)[CH:29]=[CH:30][CH:31]=2)[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]1[N:39]=[CH:38][N:37]([C:40](N2C=NC=C2)=O)[CH:36]=1.CN(C)CCN>CN(C=O)C.O>[CH3:38][N:37]([CH3:40])[CH2:36][CH2:35][NH:39][C:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:19]2[C:18]3[C:23](=[N:24][CH:25]=[CH:26][C:17]=3[NH:16][C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:15][CH:14]=3)[NH:22][C:21](=[O:27])[C:20]=12)=[O:34]
Reactant: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4c(C(=O)O)cccc4c23)cc1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cccc2c1c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Reaction time: 2 h

Procedure:
434 (20 mg, 0.04 mmol), and CDI (14 mg, 0.09 mmol) were suspended in DMF (1 mL), and stirred for 2 h. N,N-dimethylethane-1,2-diamine (8 mg, 0.09 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with H2O. The resulting precipitate was filtered, washed with MeOH, and dried under vacuum to provide 435. LC-MS (M+H=521, obsd.=521). 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 6H), 2.49 (4H), 6.93 (d, 1H), 7.20 (d, 2H), 7.54 (m, 3H), 7.76 (m, 3H), 7.97 (d, 1H), 8.10 (d, 1H), 8.27 (s, 1H), 8.85 (d, 1H), 9.18 (s, 1H), 10.27 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7](=[O:17])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1.CCN(C(C)C)C(C)C.CN([C:34]([O:38][N:39]1N=NC2C=CC=C[C:40]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.CNOC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7](=[O:17])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:39]([O:38][CH3:34])[CH3:40])=[O:16])[N:13]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(C(=O)O)cs1
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reaction time: 8 h

Procedure:
0.58 g of 2-(3-(3,4-dichlorobenzyl)ureido)thiazole-4-carboxylic acid was dissolved in 15 ml of DMF and 3.0 eq. of DIEA and 1.05 eq. of TBTU was added. To the mixture, 1.2 eq. of N,O-dimethylhydroxylamine HCl salt was added and the reaction was stirred at room temp. overnight. The product was precipitated from water, filtered, washed with water and dried to give 2-(3-(3,4-dichlorobenzyl)ureido)-N-methoxy-N-methylthiazole-4-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[ClH:12].[CH2:13]([NH2:15])[CH3:14].C([BH3-])#N.[Na+]>CO>[ClH:12].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:15][CH2:13][CH3:14])[CH3:10])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CC(=O)Cc1ccc(Br)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNC(C)Cc1ccc(Br)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
A mixture of 1-(4-bromophenyl)propan-2-one (5 grams, 23.5 mmole), ethylamine hydrochloride (19 grams, 0.23 mole) and sodium cyanoborohydride (2.22 grams, 0.035 mole) in methanol (100 ml) was stirred at 22° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between 1.0N sodium hydroxide (25 ml) and ethyl ether (60 ml). The organic phase was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The oily base was converted to the hydrochloride salt and recrystallized from ethanol/ethyl ether to give [2-(4-bromophenyl)-1-methylethyl]ethylamine hydrochloride (3.8 grams, 58%), m.p. 175-176° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].CO[C:12](=[O:23])[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=1.Cl>O1CCCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:17]([C:16]1[CH:15]=[CH:14][C:13]([C:12](=[O:23])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:22][CH:21]=1)=[O:19]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1ccc(C(=O)CC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
In a 2 l four-necked flask equipped with a mechanical stirrer, dropping funnel, thermometer, reflux condenser, and a nitrogen-inlet tube, 32 gm (0.8 mol) of 60% sodium hydride, 79 gm (0.79 mol) of pinacolone, and 700 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream. To this solution, 70 gm (0.36 mol) of dimethylterephthalate in 300 ml of tetrahydrofuran was added dropwise over one hour. After the addition, the reaction mixture was refluxed with heating for 6 hours, and was cooled to room temperature. After addition of 180 ml of 2N aqueous hydrochloric acid, the reaction mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give a crude product. The crude product was recrystallized using hexane to obtain 78 gm of the target compound as colorless scales (yield: 66%).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([C:12]#[N:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(O)C>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([CH2:12][NH2:13])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: NCC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 10 g (40 mmol) 1-diphenylmethylazetidin-3-carbonitrile in 20 ml abs. THF are added dropwise at RT to a suspension of 3.1 g (80 mmol) lithium aluminum hydride in 80 ml abs. THF and stirred overnight, 2 ml ethanol are carefully added to the batch and the batch is filtered. The filtrate is concentrated under vacuum and dispersed between CHCl3 and water. The aqueous phase is extracted twice, each with 50 ml CHCl3, and the combined organic phases are dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH/NH4OH (90/10/0 to 90/10/1). Yield: 5.6 g (57%) of slowly solidifying resin.
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)[C:17]2[NH:26][C:27]4[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=4[C:16]=2[CH2:15][CH2:14]3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[CH3:34][O:33][C:31]1[CH:32]=[C:27]2[C:28]([CH2:16][CH2:15][C:14](=[O:3])[N:26]2[CH3:17])=[CH:29][CH:30]=1
Reactant: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccc2c(c1)N(C)C(=O)CC2

Procedure:
Under nitrogen, combined 3.2 g of 7-Hydroxy-3,4-dihydro-1H-quinolin-2-one (0.0196 mol) with 25 ml of THF. Added 5.1 g of potassium t-butoxide (0.0451 mol) and stirred for 1.25 hours. Added 4.3 ml of dimethyl sulfate (0.0451 mol), followed by 10 ml of THF and stirred overnight. The reaction mixture was diluted with EtOAc and extracted three times with H2O, dried (MgSO4), and evaporated under reduced pressure. Purified by chromatography on Biotage Flash 40, eluting with 3:1 Hexanes/EtOAc to give 1.7 g of white solid (45%). 1H NMR (400 MHz, CDCl3) δ 2.62 (2H, q, J=5.39 Hz), 2.83 (2H, q, J=6.85 Hz), 3.32 (3H, s), 3.81 (3H, s), 6.53 (1H, d, J=2.49 Hz), 6.54 (1H, d, J=1.87 Hz), 7.05 (1H, d, J=7.68 Hz). M/z (APCI+) 192.1 (M+1). HPLC (aqueous 200 mM ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 uM, 125×4 mm column) 4.068.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH2:30]>C(Cl)Cl>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH:30][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: NCc1cccs1
Reactant: OCCCSc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1csc(CNCCCSc2ccncc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 290.9 %

Procedure:
In 200 ml of methylene chloride were dissolved 10.34 g (61.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 10.2 ml (73.3 mmol) of triethylamine, methanesulfonyl chloride [5.7 ml (73.3 mmol)] was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried. Then the solvent was distilled off. To 8.05 g of the residue was added 3.3 ml (3.25 mmol) 2-thiophenemethylamine. The mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 2.5 g of the desired compound (yield: 29.1%, yellow oil).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]2[CH:21]=[C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[O:19][N:18]=2)[N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:27][C:24]1[S:23][C:22]([C:20]2[O:19][N:18]=[C:17]([CH2:16][N:7]3[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([C:11]4[S:12][CH:13]=[CH:14][CH:15]=4)=[N:8]3)[CH:21]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(-c2cccs2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2cccs2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 4 g 2-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester in 20 ml THF, 10 ml water and 500 mg lithium hydroxide monohydrate were added. After stirring for 2 h at 60° C. the reaction was cooled to RT. The mixture was acidified with half concentrated hydrochloric acid to pH 3 and the precipitate collected by filtration and washed with 10 ml water. The product was obtained as a white solid which was dried under reduced pressure. Yield: 3.8 g.
Reaction SMILES: [Si]([O:18][C:19]1[CH:53]=[CH:52][C:22]([O:23][CH2:24][C@@H:25]([OH:51])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:50]=[CH:49][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[S:44][CH:45]=[CH:46][C:47]=4[CH3:48])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:51][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:53][CH:52]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:50]=[CH:49][C:33]([NH:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([C:43]3[S:44][CH:45]=[CH:46][C:47]=3[CH3:48])=[O:42])[CH2:39][CH2:40]2)=[CH:32][CH:31]=1
Reactant: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 84.7 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}(3-methyl-2-thienyl)methanone (0.083 g, 0.111 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.048 g, 0.094 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)(=[O:3])[CH3:2].C(OO)(=[O:14])C>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N+:6]=1[O-:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Br)n1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(Br)[n+]1[O-]
Reaction time: 19 h
Yield: 83 %

Procedure:
More specifically, the mercapto pyridine-1-oxide derivatives of the instant invention are prepared from known starting materials. 2-amino-6-bromopyridine which may be prepared by hydrogen bromide induced cyclization of 3-hydroxyglutaronitriles, a method described in U.S. Pat. No. 3,096,337, or by any other known process, is dissolved in an excess amount of acetic anhydride and heated at 70° C. for 45 minutes and the excess acetic anhydride is hydrolyzed by the addition of 300 ml. water, to give a substantially quantitative yield (95%) of 2-acetamido-6-bromopyridine which has a melting point of 159.2°-160.0° C. The 2-acetamido-6-bromopyridine is oxidized by heating a solution thereof in glacial acetic acid with an excess of peracetic acid at 70° C. for 2 hours and at 55° C. for 19 hours. The reaction mixture is diluted with 1600 ml. water and concentrated in vacuum, unreacted material removed by filtration, and the solvent evaporated from the filtrate, giving an 83% yield of impure 2-acetamido-6-bromopyridine-1-oxide which is purified and recrystallized from 2-propanol to yield fine white needles having a melting point of 180.0°-180.5° C. The mercapto derivative of 2-acetamido-6-bromopyridine-1-oxide may be prepared by reaction with an excess of sodium hydrosulfide (1 M NaSH) in an aqueous-ethanol medium while stirring for 5 hours at 60° C. and overnight at room temperature, adding concentrated hydrochloric acid dropwise to the cold yellow solution and collecting the light yellow solid by filtration, purifying by recrystallization from 2-propanol and obtaining pale yellow crystals having a melting point of 172.8°-173.5° C. A 79% yield of 2-acetamido-6-mercaptopyridine-1-oxide is obtained with the aforedefined process.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:20]2)[C@H:16]([C:30](OCC)=[O:31])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:18][C@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:20][CH2:21]2)[C@H:16]([CH2:30][OH:31])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1([C@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Temperature: -15 °C
Yield: 93.4 %

Procedure:
Under a nitrogen atmosphere, lithium aluminum hydride (195.6 mg, 5.153 mmol) was suspended in anhydrous tetrahydrofuran (40 ml) to which, while stirring at −15° C., was subsequently added dropwise an anhydrous tetrahydrofuran (10 ml) solution of ethyl cis-1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine-3-carboxylate (1.001 g, 2.577 mmol) over a period of 15 minutes. The reaction suspension was stirred for 3.5 hours in an ice bath, gradually mixed with cold water (5 ml) and then stirred for an additional 15 minutes at room temperature. The reaction suspension was filtered through celite (diethyl ether washing), and the resulting filtrate was concentrated under reduced pressure and dried, to thereby obtain 833.9 mg (93.4%) of the title compound as a colorless oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[S:27][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: c1cscn1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3nccs3)c2)c1

Procedure:
This compound was prepared by method C using compound 12b and thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[NH:8]C(=O)C.Cl.[CH3:17]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([O:15][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CO
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1Cl
Agent: Cl
Product: COC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-chloro-4-acetamidophenylacetic acid (180 grams, 0.79 moles) in methanol (2 L), was treated with concentrated HCl (200 mL) and the resulting solution refluxed for 6 hours and then stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to about one-half its volume and ether (4 L) was added. The resulting precipitate was filtered, washed with ether and dried to give the title compound (173 grams) as a tan solid NMR, (CD3OD): δ3.70 (s, 2H); 3.73 (s, 3H); 7.35 (d, 1H); 7.43 (d, 1H); 7.56 (s, 1H).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[I:10][C:11]1[CH:18]=[CH:17]C(CBr)=[CH:13][CH:12]=1.[OH-].[K+].O>C1(C)C=CC=CC=1>[I:10][C:11]1[CH:18]=[CH:17][C:9]([CH2:2][O:3][CH2:4][C@H:5]([OH:6])[CH2:7][OH:8])=[CH:13][CH:12]=1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: BrCc1ccc(I)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: OC[C@@H](O)COCc1ccc(I)cc1
Yield: 88.9 %

Procedure:
(S)-(+)-2,2-Dimethyl-1,3-dioxolane-4-methanol (6, 1.17 g, 8.9 mmol) and 4-iodobenzylbromide (2.5 g, 8.4 mmol) were refluxed under Dean-Stark conditions in toluene (80 mL) in the presence of KOH (8.8 g, 154.0 mmol) for 12 h. The reaction mixture was allowed to cool down and H2O (30 mL) was added. After separation of the phases the water layer was washed with toluene (2×15 mL). Combined organic layers were washed with H2O (30 mL) and concentrated in vacuo. The residue was treated with 80% aq. AcOH (25 mL) for 48 h at rt. The solvent was removed in vacuo and the residue was co-evaporated twice with toluene/EtOH (30 mL, 5:1, v/v). The residue was dried under diminished pressure to afford (R)-3-(4-iodobenzyloxy)propane-1,2-diol (7, 100%, 2.3 g) as yellowish oil that was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:18][C:19]1[S:23][N:22]=[C:21]([CH3:24])[CH:20]=1)#[N:2].C([O-])([O-])=[O:26].[K+].[K+].OO>CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:26])=[C:4]([NH:18][C:19]2[S:23][N:22]=[C:21]([CH3:24])[CH:20]=2)[CH:5]=1)[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C#N)sn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C(N)=O)sn1
Reaction time: 0.08 h
Yield: 29.8 %

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-4-methylpentanamide (102 mg, 0.297 mmol) in DMSO (2 mL), K2CO3 (200 mg, 1.45 mmol) and H2O2 (50% aq., 1.00 mL) were added. After being stirred at 100 C for 5 min, the mixture was purified by HPLC to give the titled compound (32 mg). MS 362.4 (M+H); UV 226.6, 275.5, 303.2 nm
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[CH:10]=1.[NH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([CH2:17][NH:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH:3]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=Cc1cc(F)cc2c1cnn2C1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(CCNCc1cc(F)cc2c1cnn2C1CCCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
To a solution of 6-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde (175 mg, 0.71 mmol) in MeOH (7 mL) was added tert-butyl N-(2-aminoethyl)-N-methyl-carbamate (184 mg, 1.06 mmol). The reaction was stirred at RT for 4 h, and then NaBH4 (35.4 mg, 0.92 mmol) was added. The reaction mixture was stirred at RT for 4 h and water was added. MeOH was removed under reduced pressure and the residue was diluted with 1N NaOH solution. The aqueous solution extracted with twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to obtain crude tert-butyl (2-(((6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methyl)amino)ethyl)(methyl)carbamate (300 mg, quantitative yield). MS (ESI) m/z: 407.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:35]=[CH:34][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][C:17]=3[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:34][CH:35]=2)=[O:10])=[CH:36][CH:37]=1
Reactant: CN(C)Cc1cc(CC(=O)OC(C)(C)C)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
To tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-((dimethylamino)methyl)phenyl)acetate (0.005 g, 0.010 mmol) in dichloromethane (1.0 ml) was added TFA (1.0 ml) and the reaction stirred for 1 hour at ambient temperature. The reaction was concentrated to give 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-((dimethylamino)methyl)phenyl)acetic acid (0.005 g). MS −465.1 [M−1].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P(Cl)(Cl)Cl.[C:17]([OH:26])(=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:11]=[C:10]([NH:12][C:17](=[O:26])[C:18]2[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=2)[OH:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:26])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]
Reactant: COC(=O)c1ccc(N)cc1N
Reactant: O=C(O)c1ccccc1O
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccccc2O)cc1NC(=O)c1ccccc1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
In 200 ml of pyridine was dissolved 8.3 g of methyl 2,4-diaminobenzoate, and to the solution was added a solution of 4.4 ml of phosphorus trichloride in 30 ml of pyridine under cooling with ice, followed by stirring at 50° to 70°C for one hour. To the mixture was added 21 g of salicylic acid was added, followed by heating at 90°C for three hours. After the cooling of the mixture by allowing it to stand, undissolved substances were filtered off and the filtrate was subjected to concentrate under reduced pressure. The concentrate was added to cold diluted hydrochloric acid to precipitate crystals. The crystals were recovered by filtration, washed with water and recrystallized from an acetone-dioxane-water mixture to obtain 11.1 g of methyl 2,4-bis(salicylamido)-benzoate having a melting point between 259° - 260°C. It was confirmed that the product was identical to that obtained in Example 7.