Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].S(=O)(=O)(O)[OH:22].[OH-].[Na+]>C(O)(=O)C.O>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][C:10]2[C:11](=[O:22])[NH:12][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][C:9]=2[CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(C(F)(F)F)cc1Sc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2Sc2cc(C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
2-(2-Aminophenylthio)-4-trifluoromethylbenzonitrile (12.5 g, 42.5 mmol) in glacial acetic acid (135 ml), water (135 ml), and concentrated sulphuric acid (135 ml) was heated to 125°-130° C. for 2.5 hr before being cooled and added to 1.5 l of ice-water and adjusted to pH 4 with sodium hydroxide solution (10N, 480 ml). The product was extracted into chloroform (1 l), dried (Na2SO4) and evaporated in vacuo. The light brown oil was placed in xylene (800 ml) and refluxed for 18 hr in a Dean-Stark apparatus. The title compound was obtained as off-white crystals (7.8 g. m.p. 216°-217° C., Rf 0.28, hexane/EtOAc 2:1) after reducing the volume to approximately 450 ml and allowing the solution to cool.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([O:12][CH3:13])[N:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[I:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:12][CH3:13])[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(I)ccnc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nccc(I)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of methyl 4-iodo-2-methoxynicotinate (10 g) in methanol (136 mL) was added 1N aqueous sodium hydroxide solution (136 mL) under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to evaporate the methanol, and the remaining aqueous solution was washed twice with diethyl ether. The obtained aqueous layer was acidified with 1N hydrochloric acid (about 30 mL), and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (7.7 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(C)(=O)=O)c1

Procedure:
A mixture of 7.7 g (0.023 mol) of 4-benzyloxy-3-(N-methylsulphonylamino)-phenyl acetate, 4.75 g (0.035 mol) of crushed potassium carbonate and 3.3 ml (0.0276 mol) of benzyl bromide in 150 ml of anhydrous acetone is stirred at reflux temperature for 4 hours. After filtration and evaporation, the compound of the title is obtained, which is recrystallized in ethyl acetate.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8]([C:10]1[C:11]([CH2:34][CH2:35]O)=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[CH:17][C:16]([O:30][CH3:31])=[C:15]([O:32][CH3:33])[CH:14]=2)=[O:9])[CH3:6].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH2:5]([O:7][C:8]([C:10]1[C:11]([CH2:34][CH2:35][Br:2])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[CH:17][C:16]([O:30][CH3:31])=[C:15]([O:32][CH3:33])[CH:14]=2)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1c(CCO)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(CCBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
Phosphorus tribromide (PBr3) (1.0 g) was added drop by drop to a solution of 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)-quinoline-3-carboxylic acid ethyl ester (1.7 g) in benzene (50 ml) at room temperature. After stirring at 80° C. for 1 hour, the reaction mixture was poured over ice water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with chloroform. The chloroform layer was washed with water and then dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (1:1, v/v) to yield 2-(2-bromoethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester (0.49 g, 26%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 132 to 133° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[Br:32]N1C(=O)CCC1=O>C(#N)C.O>[Br:32][C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 67.7 %

Procedure:
To a solution of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.100 g, 0.235 mmol) (as prepared in Ex. 2, Part D) in anhydrous acetonitrile (5 mL) was added N-bromosuccinimide (0.042 g, 0.235 mmol) and the mixture was heated at 85° C. for 5 h. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to afford crude product which was purified by preparative TLC (gradient of ethyl acetate and petroleum ether) to afford (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (80 mg, 0.159 mmol, 68% yield) as an off-white solid. LC/MS (ESI) m/e 504.2 [(M+H)+, calcd for C24H31BrN3O4 504.1]; LC/MS retention time (method A): tR=2.23 min.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH3:11].C(=O)([O-])O.[Na+].[CH2:25]([NH2:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH2:25]([N:31]1[CH2:2][CH:3]2[CH:5]([C:4]2([C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:18]#[N:19])[CH3:11])[C:6]1=[O:8])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCN
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C#N)c1
Temperature: 25 °C
Yield: 35.2 %

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-(3-cyanophenyl)-2-methylcyclopropane-carboxylate (Preparation 35, 5.82 g, 21.1 mmol) in N,N-dimethylformamide (20 ml) at room temperature was added sodium hydrogen carbonate (1.77 g, 21.1 mmol) followed by hexylamine (16.7 ml, 0.13 mol). The mixture was then heated under reflux for 16 h, cooled to room temperature and poured onto ice. After warming to room temperature, the mixture was partitioned against diethyl ether (50 ml). The two layers were separated and the aqueous layer was extracted with diethyl ether (2×30 ml). The ethereal extracts were washed with water (50 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude oil was purified by silica column chromatography eluting with a gradient of hexane:ethyl acetate (5:1 to 0:100) to afford the title compound (2.2 g, 35%) as a colourless oil.
Reaction SMILES: [NH2:1]C(OCC)=O.[F-].[K+].[CH3:9][O:10][CH2:11][CH:12]1[CH2:16][O:15][C:14](=O)[O:13]1>CS(C)=O>[CH3:9][O:10][CH2:11][CH:12]1[O:13][C:14](=[O:15])[NH:1][CH2:16]1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(N)=O
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCC1CNC(=O)O1
Temperature: 140 °C
Reaction time: 77 h
Yield: 68.9 %

Procedure:
Urethane (82.4 g, 0.925 mol) was dissolved in dimethyl sulfoxide (400 mL), and thereto were added potassium fluoride (48.8 g, 0.841 mol) and 4-methoxymethyl-1,3-dioxolan-2-one (111 g, 0.841 mol), in order. The mixture was stirred for 77 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by distillation to give the subject 5-methoxymethyloxazolidin-2-one (76.0 g, yield 68.9%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:21])[S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:22]1[S:23][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25][N:26]=1)=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CN(C)C=O.C(OCC)(=O)C>[CH3:21][N:11]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(=[O:14])=[O:13])[C:9]1[CH:10]=[C:2]([O:1][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6]([C:22]1[S:23][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25][N:26]=1)=[CH:5]2
Reactant: CCOC(=O)CBr
Reactant: CN(c1cc(O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a solution of N-{5-hydroxy-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (800 mg) in N,N-dimethylformamide (10 mL) were added potassium carbonate (264 mg) and ethyl bromoacetate (0.18 mL), and the mixture was stirred at 50° C. for 6 hr. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=85:15-0:1) to give the title compound (724 mg, yield 76%) as a pale-yellow powder. MS: 590(MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.OS(O)(=O)=O.[N+:19]([O-])([O-:21])=[O:20].[K+]>C1C=CC=CC=1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([N+:19]([O-:21])=[O:20])=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2
Reactant: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: c1ccccc1
Product: O=C1Nc2c([N+](=O)[O-])cc(Cl)c(Cl)c2C1=O

Procedure:
To a solution of 4,5-dichloroisatin (13f, 430 mg, 2.0 mmol) in cone H2SO4 (5 mL) was added powdered KNO3 (300 mg, 2.5 mmol) at 0° C. in portions with stirring. The mixture was stirred at 22° C. for 16 h, poured into ice-H2O (50 mL). The precipitate was filtered, washed with H2O (5×10 mL) and dried to give 295 mg (54%) of 13 h as a yellow powder. The analytical sample was obtained by crystallization from benzene, mp 204°-5° C. IR 1776, 1768, 1749, 1614, 1473, 1340, 1227 cm-1 ; 1H NMR δ 11.932 (s, 1H), 8.535 (s, 1H). HRMS Calcd for C8H2Cl2N2O4 : 259.9391; Found: 259.9389.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[CH2:19][C:18]1=[O:26]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:19]1[C:20]2[C:25](=[N:24][CH:23]=[CH:22][CH:21]=2)[NH:17][C:18]1=[O:26])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2cccnc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ncccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was methylated and then formylated. The aldehyde was condensed with 7-aza-2-oxindole to give 0.2 g of 3-(3,5-diisopropyl-4-methoxy-benzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[O:10][CH:9]([CH2:25][O:26]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:8]1.[CH3:37][O-].[Na+]>>[CH3:37][O:26][CH2:25][CH:9]1[O:10][C:11]2([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:16][CH2:17]2)[CH2:12][N:7]([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:8]1
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(c3ncccn3)CC3(CCN(C(=O)OC(C)(C)C)CC3)O2)cc1
Agent: [Na+]
Product: COCC1CN(c2ncccn2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1

Procedure:
Tert-butyl 4-(pyrimidin-2-yl)-2-(tosyloxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1.83 g, 3.53 mmol) was dissolved in a solution of sodium methoxide (71 mL of 0.5 M in methanol, 35 mmol) and refluxed for 18 h. The solvent was evaporated to dryness and the residue dissolved in dichloromethane (200 mL). The solution was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (5-80% ethyl acetate/hexanes) provided tert-butyl 10-(methoxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate as colorless oil. ESI-MS m/z calc. 378.2. found 379.3 (M+1)+; Retention time: 1.54 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 8.31 (d, J=4.8 Hz, 2H), 6.58 (t, J=4.8 Hz, 1H), 4.72-4.52 (m, 2H), 3.91 (ddd, J=10.9, 7.9, 4.9 Hz, 1H), 3.76-3.59 (m, 2H), 3.56-3.44 (m, 2H), 3.40 (s, 3H), 3.13 (t, J=11.1 Hz, 1H), 2.85-2.65 (m, 2H), 1.98 (d, J=14.6 Hz, 2H), 1.59 (dd, J=8.7, 4.5 Hz, 2H), 1.45 (s, 9H), 1.44-1.37 (m, 1H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]1[C:11]([CH2:12]Cl)=[CH:10][CH:9]=[CH:8][C:7]=1[S:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.[Cl-].[Na+]>CS(C)=O>[CH3:4][O:5][C:6]1[C:7]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1c(CCl)cccc1Sc1ccccc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Sc1ccccc1C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Powdered sodium cyanide (1.5 g) was added all at once to a solution of o-tolyl 2-methoxy-3-chloromethylphenyl thioether (8.3 g) in dimethyl sulfoxide (40 ml), and the mixture was stirred for 15 minutes, poured into saturated aqueous solution of sodium chloride and extracted with diethyl ether. The extract was washed with water, dried and then evaporated under reduced pressure to give oily 2-[2-methoxy-3-(o-tolylthio)phenyl]acetonitrile (7.7 g).
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[O:11][CH2:10][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:12][O:13]2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCC1COC(c2ccc(Br)cc2)OC1

Procedure:
Quantities: compound from Example 9 (48.3 g, 0.26 mol), 4-bromobenzaldehyde (46.5 g, 0.25 mol) and 4-toluenesulphonic acid (150 mg). The experimental procedure was as described in Example 11.
Reaction SMILES: C([O:3][P:4]([CH2:9][NH:10][C:11]([C:13]1[S:17][C:16]([NH2:18])=[N:15][C:14]=1[CH3:19])=[O:12])(=[O:8])[O:5]CC)C.[CH:20]([O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH:32]=1)[C:27](O)=[O:28])([CH3:22])[CH3:21]>>[CH:20]([O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH:32]=1)[C:27]([NH:18][C:16]1[S:17][C:13]([C:11]([NH:10][CH2:9][P:4](=[O:8])([OH:3])[OH:5])=[O:12])=[C:14]([CH3:19])[N:15]=1)=[O:28])([CH3:22])[CH3:21]
Reactant: CCOP(=O)(CNC(=O)c1sc(N)nc1C)OCC
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Product: Cc1nc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2)sc1C(=O)NCP(=O)(O)O

Procedure:
The title compound is prepared from {[(2-amino-4-methyl-thiazole-5-carbonyl)-amino]-methyl}-phosphonic acid diethyl ester and 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid in a similar manner to Example 21.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]([S:18][C:19]2[CH:24]=[C:23]3[O:25][CH2:26][O:27][C:22]3=[CH:21][C:20]=2I)=[N:16][C:10]2[C:11]([NH2:15])=[N:12][CH:13]=[N:14][C:9]1=2)[CH3:3].C([N:36]1[CH:40]=[CH:39][CH2:38][CH2:37]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:36]1[CH2:40][CH:39]=[CH:38][CH:37]1[C:20]1[C:19]([S:18][C:17]2[N:8]([CH2:7][CH2:6][CH2:5][NH:4][CH:2]([CH3:3])[CH3:1])[C:9]3[C:10]([N:16]=2)=[C:11]([NH2:15])[N:12]=[CH:13][N:14]=3)=[CH:24][C:23]2[O:25][CH2:26][O:27][C:22]=2[CH:21]=1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2C2C=CCN2)OCO3)nc2c(N)ncnc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
A solution of PU-H71 (30 mg, 0.0585 mmol) and N-Boc-2,3-dihydro-1H-pyrrole (19.8 mg, 20.2 μL, 0.117 mmol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 μL, 0.117 mmol) and Pd(PPh3)4 (13.5 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 100° C. for 20 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 15:1) and the resulting residue was dissolved into 2 mL of CH2Cl2:TFA (4:1) and stirred for 1 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 10:1) to give 6.0 mg (23%) of DZ3-141. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.19 (s, 1H), 6.98 (s, 2H), 6.04 (m, 1H), 6.01 (s, 2H), 5.74 (m, 1H), 5.62 (d, J=2.0 Hz, 1H), 4.31 (t, J=6.9 Hz, 2H), 3.81-3.88 (m, 1H), 3.89-3.95 (m, 1H), 2.87 (septet, J=6.3 Hz, 1H), 2.68 (t, J=6.7 Hz, 2H), 2.14 (m, 2H), 1.15 (d, J=6.3 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for C22H28N7O2S, 454.2025; found. 454.2046; HPLC: method A Rt=5.27, method B Rt=2.72.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:28]=[CH:27][C:26]([N:29]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][C:10]=1[C:11]([O:13][CH2:14][C:15]([O:17]CC1C=CC=CC=1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([O:8][C:9]1[CH:28]=[CH:27][C:26]([N:29]([CH2:34][CH:35]2[CH2:36][CH2:37]2)[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][C:10]=1[C:11]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)O
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A mixture of 2-(benzyloxy)-2-oxoethyl 2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)methylsulfonamido)benzoate (0.288 g, 0.540 mmol) and 10% w/w Pd/C (0.030 g, 0.028 mmol) in MeOH (20 ml) and EtOAc (5 ml) was hydrogenated at 20 psi for 3 hours. The catalyst was filtered off and the solvent was removed affording 2-(2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)-methylsulfonamido)benzoyloxy)-acetic acid (0.215 g, 0.485 mmol, 90% yield). This product was used without purification.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([CH:12]2[O:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:21][C:15]=3[NH:14][CH2:13]2)=[O:11])[C:6]([C:27]#[C:28][CH2:29]O)=[CH:5][C:4]=1[CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[CH2:39]([N:41](CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.CN>ClCCl>[CH:31]1([C:4]2[C:3]([OH:2])=[CH:8][C:7]([NH:9][C:10]([CH:12]3[O:17][C:16]4[CH:18]=[CH:19][C:20]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:21][C:15]=4[NH:14][CH2:13]3)=[O:11])=[C:6]([C:27]#[C:28][CH2:29][NH:41][CH3:39])[CH:5]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCN(CC)CC
Reactant: COC(=O)Oc1cc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(C#CCO)cc1C1CCCC1
Agent: CN
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Product: CNCC#Cc1cc(C2CCCC2)c(O)cc1NC(=O)C1CNc2cc(OC(F)(F)F)ccc2O1
Temperature: 25 °C
Reaction time: 10 h
Yield: 116 %

Procedure:
2-Cyclopentyl-4-(3-hydroxyprop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate (20 mg, 0.037 mmol) was dissolved in dichloromethane (1 mL) and triethylamine (20 μL, 0.14 mmol) and cooled to 0° C. Methanesulfonyl chloride (4.3 mg, 2.9 μL, 0.04 mmol) in 1 mL of dichloromethane was slowly added to the reaction. Conversion to the mesylate was complete after 10 min. MeNH2 (100 μL of 2 M in THF, 0.20 mmol) was then added and the reaction stirred at room temperature for 10 h. The solution was concentrated in vacuo and purified by HPLC (10-99% CH3CN/0.035% TFA) to provide N-(4-cyclopentyl-5-hydroxy-2-(3-(methylamino)prop-1-ynyl)phenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (21 mg, 97% yield). LC/MS m/z 490.4 [M+H]+. 1H NMR (400.0 MHz, MeOD) S 7.65 (s, 1H), 7.28 (s, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.60 (s, 1H), 6.54 (dd, J=1.8, 8.7 Hz, 1H), 4.78 (dd, J=3.0, 7.0 Hz, 1H), 4.14 (dd, J=16.6, 27.1 Hz, 2H), 3.67 (dd, J=3.0, 12.1 Hz, 1H), 3.49-3.44 (m, 1H), 3.24 (m, 1H), 2.79 (s, 3H), 2.05-1.92 (m, 2H), 1.81-1.77 (m, 2H), 1.71-1.68 (m, 2H), 1.54-1.51 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C@@H:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])=[C:4]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:3]=1>CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH:10]([NH:12][C:13]3[N:21]=[CH:20][N:19]=[C:18]4[C:14]=3[N:15]=[CH:16][NH:17]4)[CH3:11])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:4]=2[CH:3]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1ccc(F)cc1Nc1ccccn1
Solvent: CC(=O)O
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 80 °C
Yield: 53.1 %

Procedure:
A mixture of (S)—N-[4-fluoro-2-(pyridin-2-ylamino)phenyl]-2-(9H-purin-6-ylamino)propionamide (130 mg, 0.332 mmol) in AcOH (1 mL) was heated for 2 h at 80° C. A second portion of (S)—N-[4-fluoro-2-(pyridin-2-ylamino)phenyl]-2-(9H-purin-6-ylamino)propionamide (136 mg, 0.347 mmol) in AcOH (5 mL) was heated for 2 h at 100° C. The two crude reaction mixtures were combined and the volatiles removed in vacuo. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic layer was washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) then triturated in MeOH/diethyl ether to afford 182 as an off-white solid (66 mg, 26%). LCMS (Method K): RT 2.94 min [M+H]+ 375.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.89 (1H, br s), 8.61 (1H, br s), 8.20-7.80 (4H, m), 7.79-7.67 (2H, m), 7.52-7.43 (1H, m), 7.20-7.08 (2H, m), 5.86 (1H, br s), 1.63 (3H, d, J=6.82 Hz)