Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:32])[NH:21][CH2:22][CH2:23][N:24]4[C@H:29]([CH3:30])[CH2:28][CH2:27][CH2:26][C@@H:25]4[CH3:31])[CH:17]=[CH:16][C:15]=3[F:33])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[F:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[C:41]([O:43]C)=[O:42]>>[CH3:30][C@H:29]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH3:31])[N:24]1[CH2:23][CH2:22][NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]([F:33])=[C:14]([NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:37]4[CH:38]=[CH:39][C:40]([C:41]([OH:43])=[O:42])=[C:35]([F:34])[CH:36]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[CH:19]=1)=[O:32]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)O)c(F)c4)ccn23)c1

Procedure:
The title compound was prepared from 7-bromo-N-(5-(2-(2,6-cis-dimethylpiperidin-1-yl)ethylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (Intermediate 4C) and 3-fluoro-4-(methoxycarbonyl)phenylboronic acid analogously to Example 1.20;
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH2:20][CH2:21][C:22]#[N:23]>>[F:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:22]([NH2:23])[C:21]([CH2:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])=[CH:4]2
Reactant: Nc1ccc(F)cc1C=O
Reactant: COc1cccc(F)c1CCC#N
Product: COc1cccc(F)c1Cc1cc2cc(F)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-fluorobenzaldehyde and 3-(2-fluoro-6-methoxyphenyl)propionitrile. Reaction temperature 100° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH:30]1[CH:37]=[CH:36][C:34]([NH2:35])=[N:33][C:31]1=[O:32].C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl.CN(C)C=O.O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:35][C:34]2[CH:36]=[CH:37][NH:30][C:31](=[O:32])[N:33]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cc[nH]c(=O)n2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 14, 150 mg, 0.439 mmol) in methylene chloride (2 mL) was treated with N,N-dimethylformamide (2 drops) and then cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (0.042 mL, 0.483 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with a mixture of cytosine (102 mg, 0.922 mmol) and N,N-diisopropylethylamine (0.191 mL, 1.098 mmol) in N,N-dimethylformamide (2 mL). The resulting reaction mixture was allowed to stir at 25° C. overnight. The reaction mixture was then diluted with water (30 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (30 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 20/1 methylene chloride/methanol) afforded impure 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-propionamide (25 mg) as a pale yellow solid. Re-purification by recrystallization from chloroform afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-propionamide (12 mg, 6.5%) as a white solid: mp 256-258° C. (dec); FAB-HRMS m/e calcd for C19H22N4O6S (M+H)+ 435.1338, found 435.1334.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH:9]=[CH2:10])=[C:7]([Cl:11])[CH:6]=[CH:5][C:3]=1[NH2:4]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[C:8]([CH2:9][CH3:10])=[C:7]([Cl:11])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: C=Cc1c(Cl)ccc(N)c1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1c(Cl)ccc(N)c1Cl
Reaction time: 2 h

Procedure:
To a solution of 2,4-dichloro-3-vinylaniline (4.9 g, 26 mmol) in EtOAc (60 mL) is added 10% Pd/C (0.50 g). The pressure flask is filled with H2 at 55 psi and shaken for 2 hrs. Excess H2 is removed and the mixture is filtered through a pad of celite. The solvent is removed and the resulting mixture is purified through a flash chromatographic column with a gradient of hexanes/ether to give 2,4-dichloro-3-ethylaniline.
Reaction SMILES: CC1(C)[O:7][C@@H:6]2[C@H:8]([OH:13])[C@H:9]([OH:12])[CH2:10][O:11][C@H:5]2[CH2:4][O:3]1.Cl>CO>[OH:3][CH2:4][C@H:5]1[C@H:6]([OH:7])[C@H:8]([OH:13])[C@H:9]([OH:12])[CH2:10][O:11]1
Reactant: CC1(C)OC[C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2O1
Agent: Cl
Solvent: CO
Product: OC[C@@H]1OC[C@@H](O)[C@@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
To a solution of (+)-(4aS,7R,8R,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (28 mg, 0.14 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.4 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1H at ambient temperature and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH:20]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:31][C:28]4[CH:27]=[CH:26][C:25]([C:21]5[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=5)=[CH:30][CH:29]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3cnc(O)nn23)cn1
Reactant: Nc1ccc(-c2cccnc2)cc1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)cn1

Procedure:
[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-pyridin-3-yl-phenyl)-amine was prepared from 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (31 mg, 26%). LCMS (m/e) 395 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.87 (s, 1H), 8.80 (s, 1H), 8.74 (s, 1H), 8.61-8.54 (m, 1H), 8.42 (d, 1H, J=8.7 Hz), 7.88 (d, 1H, J=7.8 Hz), 7.73 (d, 2H, J=8.1 Hz), 7.57 (d, 2H, J=8.1 Hz), 7.40-7.31 (m, 1H), 7.02-6.84 (m, 4H), 4.03 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>ClC1C=CC=CC=1>[N:1]1([C:2]2[C:7]3[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: ClCCNCCCl
Reactant: Nc1cccc2c1OCC(=O)N2
Agent: Cl
Solvent: Clc1ccccc1
Product: O=C1COc2c(cccc2N2CCNCC2)N1
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of intermediate 58 (164 mg, 1.0 mmol) in chlorobenzene (5 mL) was added bis(2-chloroethyl)amine hydrochloric acid (285 mg, 1.6 mmol) and the mixture was heated to reflux for 100 h. The reaction mixture was concentrated in vacuo and the residue was stirred in EtOAc for 2 h. The resulting brown solid was filtered and purified by silica gel chromatography to give 8-(piperazin-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (intermediate 59) (150 mg, 64%). HPLC: 99%, RT 1.344 min. MS (ESI) m/z 234.1[M+H]+.
Reaction SMILES: C(C1C=CC(N2CC[C@H](N[C@@H](C3C4C(=CC=CC=4)C=CC=3)C)C2)=CC=1)(=O)C.[C:28]([O:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].F[C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51]([CH3:53])[CH3:52])(=[O:50])=[O:49])=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.O>[CH3:52][N:51]([CH3:53])[S:48]([C:45]1[CH:44]=[CH:43][C:42]([N:38]2[CH2:39][CH2:40][C@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:31])([CH3:29])[CH3:30])[CH2:37]2)=[CH:47][CH:46]=1)(=[O:49])=[O:50]
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 16.9 %

Procedure:
A solution of 50 g of 4-fluorobenzenesulfonyl chloride in 250 ml of THF was cooled to 0° C., and then, 100 ml of an aqueous 50% dimethylamine solution was added dropwise thereto, and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and then the liquids were separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried, the solvent was evaporated, and disopropyl ether and hexane were added to the residue. Then, the precipitates were collected by filtration and washed with hexane to obtain 49.9 g of 4-fluoro-N,N-dimethyl-benzene sulfonamide. (2) In 600 ml of DMSO were suspended 25 g of (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine, 47.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide and 139 g of potassium carbonate, and the mixture was stirred at 130° C. for 1 day. To the reaction mixture were added water and ethyl acetate, the resulting mixture was stirred and the liquids were separated. The organic layer was washed with water, and then dried, and the solvent was evaporated. The residue was dissolved in chloroform, NH silica gel was added thereto and the mixture was allowed to stand for a while, and silica gel was filtered off. The silica gel was further washed with ethyl acetate. The filtrate and the washed solution were combined, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→67:33) to obtain 8.39 g of tert-butyl [(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]carbamate.
Reaction SMILES: [Cl:1][Pt-2:2](Cl)(Cl)[Cl:3].[K+].[K+].[NH:8]([C:10]1[NH:11][CH2:12][CH2:13][N:14]=1)[NH2:9].C([O-])(=O)C.[Na+]>O>[Pt:2]([Cl:3])[Cl:1].[NH:8]([C:10]1[NH:14][CH2:13][CH2:12][N:11]=1)[NH2:9]
Reactant: Cl[Pt-2](Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: NNC1=NCCN1
Agent: [K+]
Solvent: O
Product: Cl[Pt]Cl
Reaction time: 24 h

Procedure:
To a solution of 4.16 g of potassium tetrachloroplatinate in 15 ml of water was added a 15 ml aqueous solution containing 1.37 g of 2-hydrazino-4,5-dihydro-1H-imidazole and 0.82 g of sodium acetate. The mixture was allowed to stand at room temperature for 24 hours to give the desired complex as light brown crystals mp>290° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C:16]([OH:18])=[O:17])=[O:5])[CH3:2].Cl.[CH3:22]O>>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C:16]([O:18][CH3:22])=[O:17])=[O:5])[CH3:20]
Reactant: CO
Reactant: CCN(CC)C(=O)c1cccc2c(CC(=O)O)c[nH]c12
Agent: Cl
Product: CCN(CC)C(=O)c1cccc2c(CC(=O)OC)c[nH]c12
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of (7-((diethylamino)carbonyl)-1H-indol-3-yl)acetic acid (2.38 g, 8.68 mmol) in methanol (10 mL) is added a 10% hydrogen chloride solution in methanol (30 mL) under nitrogen atmosphere, and the mixture is refluxed for 30 minutes. The reaction solution is cooled to room temperature, and the solvent is distilled off. To the residue is added chloroform, and the mixture is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation, and the resultant crude product is purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→ethyl acetate) to give methyl (7-((diethylamino)carbonyl)-1H-indol-3-yl)acetate (1.93 g, yield: 77%).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:29]1([NH:28][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccccc1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)Nc3ccccc3)c(=O)n12
Reaction time: 0.08 h
Yield: 78.8 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -10° C. and -13° C. during 20 minutes. After stirring for 5 minutes, 9.19 g (0.088 mol) of aniline dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -10° C. and -13° C. during 30 minutes. The reaction mixture is stirred below -10° C. for 1 hour and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 17.6 g (78.8%) of the named compound as yellow crystals after recrystallization from ethanol, m.p.: 186°-188° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=O>>[OH:25][B:13]1[C@@H:12]([NH:11][C:9](=[O:10])[CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)[CH2:3][CH2:4]2)[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=2[O:14]1
Reactant: O=Cc1ccccn1
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Product: O=C(C[C@H]1CC[C@H](NCc2ccccn2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) and picolinaldehyde following the procedure in Example 27. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 438 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][C:38]([N:42]([CH2:47][C:48]3[S:49][CH:50]=[CH:51][CH:52]=3)[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:40]=2)[C:35](=[O:53])[N:34]1[CH2:54][C:55](O)=[O:56]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:55](=[O:56])[CH2:54][N:34]1[C:35](=[O:53])[C:36]2[C:41](=[CH:40][CH:39]=[C:38]([N:42]([CH2:47][C:48]3[S:49][CH:50]=[CH:51][CH:52]=3)[S:43]([CH3:46])(=[O:45])=[O:44])[CH:37]=2)[C:33]1=[O:32]
Reactant: CS(=O)(=O)N(Cc1cccs1)c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)N(Cc1cccs1)c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (200 mg, 0.476 mmol), DMAP (116 mg, 0.952 mmol), and EDC (182 mg, 0.952 mmol) in DCM (10 ml), 2-(1,3-dioxo-5-(N-(thiophen-2-ylmethyl)methylsulfonamido)isoindolin-2-yl)acetic acid (225 mg, 0.571 mmol) was added portion wise, and the resulting mixture was stirred at room temperature for 18 hours. The solvent was evaporated, and the crude was purified by flash chromatography on silica gel (DCM/MeOH 10/0.5). The resulting product was triturated with iPr2O affording after filtration 227 mg of crude desired product. A further purification by flash chromatography on silica gel (DCM/acetone 8/1) was performed to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(1,3-dioxo-5-(N-(thiophen-2-ylmethyl)methylsulfonamido)isoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (155 mg, 0.195 mmol, 40.9% yield, MS/ESI+ 796.02 [MH]+, [αD]=−30.31, c=0.415, DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (s, 2H), 7.96 (d, 1H), 7.91 (d, 1H), 7.86 (dd, 1H), 7.40 (dd, 1H), 7.19 (d, 1H), 7.08 (d, 1H), 6.92-6.99 (m, 1H), 7.08 (t, 1H), 6.86 (d, 1H), 6.84 (d, 1H), 6.00 (dd, 1H), 5.25 (s, 2H), 4.39 (s, 2H), 3.81-4.09 (m, 2H), 3.37 (dd, 1H), 3.21 (s, 3H), 3.21 (dd, 1H), 1.17-1.37 (m, 1H), 0.50-0.69 (m, 2H), 0.21-0.46 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH3:11][O:12][C:13](=[O:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:11][O:12][C:13](=[O:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18]([CH:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[O:19])=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)C2C(=O)OC(C)(C)OC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture consisting of Meldrum's acid (2 g, 13.9 mmol), terephthalic acid monomethyl ester (2.5 g, 13.9 mmol), EDC (3.5 g, 18 mmol) and DMAP (2.2 g, 18 mmol) in DCM (50 mL) was stirred at RT overnight. The reaction mixture was diluted with DCM (to ˜100 mL) then washed with water (2×50 mL). The organic solution was dried over Na2SO4 and concentrated to afford 3.9 g of crude 4-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-benzoic acid methyl ester as a yellow solid. The crude was carried on as is for the next step.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:33])[NH:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]3[N:29]=[C:30]([CH3:32])[CH:31]=[C:19]3[N:18]=2)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([O:6]C)=[O:5].[OH-].[Li+]>CO>[CH3:8][C:2]([C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:33])[NH:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:20]3[N:29]=[C:30]([CH3:32])[CH:31]=[C:19]3[N:18]=2)=[CH:13][CH:14]=1)([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(C)(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)n3nc(C)cc3n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CC(=O)O)cc3)cc(-c3ccccc3)n2n1
Reaction time: 2.5 h
Yield: 34 %

Procedure:
In a 50 ml pear flask was added methyl 3-methyl-3-(4-(2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-ylcarbamoyl)phenyl)butanoate (30 mg, 0.068 mmol) in methanol (2 ml) to give a tan solution. To this mixture at room temperature, lithium hydroxide (2N solution) (2 ml, 4.0 mmol) was added. The reaction progress was carefully monitored by UPLC because hydrolysis was a significant competing side reaction. After 2.5 h, most of the starting material has been consumed. The reaction mixture was acidified to pH˜3 with 2N HCl. The resulting suspension was partitioned between brine and ethyl acetate, and the aqueous layer was extracted one more time with ethyl acetate. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by preparatory HPLC (55-80% MeCN/H2O gradient+0.01% TFA). Lyophilization of the collected fractions gave the titled product (9.9 mg, 34% yield). 1H NMR (DMSO-d6) δ: 11.91 (s, 2H), 11.20 (s, 2H), 8.04-8.08 (m, 3H), 8.02 (d, J=8.8 Hz, 3H), 7.96 (s, 2H), 7.60-7.66 (m, 5H), 7.54 (d, J=8.8 Hz, 2H), 6.40 (s, 1H), 2.66 (s, 2H), 2.40 (s, 3H), 1.41 (s, 6H); ESI-MS: m/z 429.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10]C)[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Br[CH:16](C)C>>[CH:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH3:1])[CH:7]=1)([CH3:10])[CH3:16]
Reactant: CCCOc1ccc([N+](=O)[O-])c(C)c1
Reactant: CC(C)Br
Product: Cc1cc(OC(C)C)ccc1[N+](=O)[O-]
Yield: 98 %

Procedure:
This compound was prepared in a similar manner to that for 404b except that 2-bromopropane was deployed for the alkyl ether adduct and chromatography utilized a 0% to 15% gradient for elution to yield a yellow oil (1.87 g, 98%): TLC Rf 0.68 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.08-8.07 (d, 1H, J=8.82 Hz), 6.77-6.75 (m, 2H), 4.66-4.62 (sep, 1H, J=6.06 Hz), 2.62 (s, 3H), 1.38-1.37 (d, 6H, J=6.12 Hz). 13C NMR (150 MHz, CDCl3) δ 162.6, 141.7, 137.1, 127.6, 118.9, 112.8, 70.6, 21.84, 21.78. Elemental analysis calculated for C10H13NO3.0.06 hexanes: C, 62.10; H, 6.96; N, 6.99. Found: C, 62.45; H, 6.69; N, 7.09.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH:20]([OH:22])[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][C:20](=[O:22])[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1Cc2cccnc2C(O)C1)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC1CC(=O)c2ncccc2C1)OCc1ccccc1
Reaction time: 2 h
Yield: 31 %

Procedure:
To a stirred solution of 6-benzyloxycarbonylamino-8-hydroxy-5,6,7,8-tetrahydroquinoline, cis-trans mixture (1.02 g, 3.42 mmol) in methylene chloride (34 mL) at room temperature under nitrogen was added Dess-Martin periodinane (1.73 g, 4.45 mmol). After 2 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to yield a residue. The residue was purified by reverse phase preparative HPLC to obtain the title compound (319 mg, 31%) as a brown oil. 13C NMR (400 MHz, CDCl3) δ 194.1, 155.4, 149.8, 147.6, 138.3, 137.2, 136.0, 128.6, 128.3, 128.2, 127.5, 67.0, 46.7, 45.4, 35.4. 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J=4.4 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.36 (dd, J=4.4, 7.9 Hz, 1H), 7.26 (m, 5H), 5.02 (s, 2H), 4.34 (s, 1H), 3.29 (d, J=15.4 Hz, 1H), 3.04 (d, J=4.0 Hz, 1H), 2.99 (d, J=4.0 Hz, 1H), 2.80 (dd, J=9.2, 11.4 Hz, 1H). HPLC/MS [M+H]+, 297.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH3:7].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:8][CH:6]([CH3:7])[CH2:5][C:4]([CH3:10])([CH3:9])[CH3:3])[N:15]=[CH:14][N:13]=1
Reactant: CC(O)CC(C)(C)C
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(CC(C)(C)C)Oc1cc(Cl)ncn1
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.24 g of 4,4-dimethyl-2-pentanol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing 0.3 g of 4,6-dichloropyrimidine in tetrahydrofuran at 0° C., followed by stirring at the same temperature for 2 hours and further stirring at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate to give a crude product of 4-chloro-6-(1,3,3-trimethylbutoxy)pyrimidine.