Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:34]([C:36]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[NH2:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:35][NH:34][C:36]2[N:41]=[N:40][C:39]([C:42]3[CH:43]=[CH:44][C:45]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:46][CH:47]=3)=[CH:38][CH:37]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2ccc(NN)nn2)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(-c2ccc(NNC(=O)Cc3ccc(Cl)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a suspension of 2-(4-chlorophenyl)acetic acid (1.07 mmole), HOBT (1.07 mmole), and EDCI hydrochloride (1.61 mmole) in DMF (7 mL) were added N-(4-(6-hydrazinylpyridazin-3-yl)phenyl)methanesulfonamide (1.07 mmole) in 10 mL of DMF followed by diisopropylethylamine (3.77 mmole). The resulting mixture was stirred at room temperature for 22 hours and evaporated in vacuo. The desired product N-(4-(6-(2-(2-(4-chlorophenyl)acetyl)hydrazinyl)pyridazin-3-yl)phenyl)methanesulfonamide was precipitated out from water.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC#N>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 78 °C

Procedure:
Amine preparation: To a solution of piperidine-4-carboxylic acid ethyl ester (3.0 g) stirring in dry MeCN (30 mL) was added potassium carbonate (2.90 g) followed by benzyl bromide (2.5 mL). The mixture was warmed to 78° C. After 3 h the mixture was cooled, poured into water (100 mL) and extracted into ethyl acetate, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to give 1-benzyl-piperidine-4-carboxylic acid ethyl ester (2.17 g) as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]([CH:19]=[CH2:20])[CH2:17][N:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[NH:29])[NH2:28])[CH:22]=3)[C:15]2=[O:30])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]([CH:19]=[CH2:20])[CH2:17][N:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[NH:28])[NH2:29])[CH:22]=3)[C:15]2=[O:30])[CH2:10][CH2:9]1
Reactant: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCNCC1
Yield: 130.5 %

Procedure:
1-(1-t-Butoxycarbonylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone (1.32 g, 3.3 mmol) was stirred in 1:1 dichloromethane:trifluoroacetic acid (30 ml) for 4 h. This solvent was removed in vacuo, and 1.35 g of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone was obtained as the trifluoroacetic acid salt LRMS (M+H)+ m/z 297.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C@@H:11]3[C:6]=2[CH:5]=[C:4]([O:17]C)[CH:3]=1.Cl.N1C=CC=CC=1>O.[OH-].[Na+]>[Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C@@H:11]3[C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1
Reactant: COc1cc(Br)c2c(c1)[C@H]1CN(C)CC[C@H]1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CN1CC[C@H]2COc3c(Br)cc(O)cc3[C@H]2C1

Procedure:
A mixture of 0.5 g (±)[4aR*,10bS*]-7-bromo-1,3,4,4a,5,10b-hexahydro-9-methoxy-2-methyl-2H-[1]benzopyrano[4,3-c]pyridine and 5 g pyridine hydrochloride is heated under nitrogen at 200° for 20 minutes. The cooled reaction mixture is dissolved in water and basified with 6N NaOH. The aqueous phase is extracted with three 25 ml portions of CH2Cl2, the extracts are dried over Na2SO4, filtered, concentrated under reduced pressure, and flash chromatographed with methylene chloride/ammonia saturated methanol (10:1) to afford the title compound; m.p. HCl salt 259°-262°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]ccc2cccc(Br)c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cccc(Br)c2c1=O
Reaction time: 72 h
Yield: 94.5 %

Procedure:
A solution of (b) (180 mg, 0.8 mmol) in DMF (5 ml) was treated with potassium carbonate (140 mg) and methyl iodide (0.062 ml) and stirred for 3 days then evaporated. The residue was partitioned between dilute aqueous sodium chloride solution and dichloromethane, re-extracting with dichloromethane twice more. The combined organic extracts were dried and evaporated affording a yellow solid (180 mg, 94%).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:4][N:3]=1.[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C1COCC1>[CH3:16][O:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[S:4][N:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1c(O)nsc1Nc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1nsc(Nc2ccccc2)c1C#N
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of 3-hydroxy-5-phenylamino-isothiazol-4-carbonitrile (2.82 g, 13 mmol), triphenylphosphine (4.04 g, 15.6 mmol), methanol (0.53 ml) in THF (25 ml) was added diethyl azadicarboxylate (DEAD, 2.46 ml, 15.6 mmol) at 0° C. The mixture was stirred at ambient temperature and evaporated to give a residue. The crude product was purified on silica gel (hexane/EtOAc, 1:1) to give a yellow powder (1.26 g, 42%).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]>Br>[CH2:1]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[CH:15][CH:16]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Agent: Br
Product: CCCCn1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Yield: 99 %

Procedure:
This compound was synthesized as a white amorphous solid from 4e (144.6 mg, 0.355 mmol) in 48% aqueous HBr (3.0 mL) in 99% yield by following general procedure 1.4: 1H NMR (400 MHz, CDCl3, δH) 7.61 (s, 1H), 7.40 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 2H), 6.90 (d, J=8.9 Hz, 2H), 6.79 (d, J=8.9 Hz, 2H), 4.58 (s, 1H), 3.85 (t, J=7.2 Hz, 2H), 3.36 (dd, J=6.2, 3.9 Hz, 4H), 3.22 (dd, J=6.2, 3.9 Hz, 4H), 1.78 (dt, J=12.7, 7.5 Hz, 2H), 1.40 (td, J=14.9, 7.5 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H). MALDI-MS: 394.2 (M+H+), 416.2 (M+Na+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH:19]C(OCC2C=CC=CC=2)=O)[CH2:8][C@@H:7]1[CH3:30])=[O:5])[CH3:2]>[Pd].C(O)C.C1CCCCC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH2:19])[CH2:8][C@@H:7]1[CH3:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc3c(cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C)CCC3
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)N1c2cc3c(cc2[C@H](N)C[C@@H]1C)CCC3
Temperature: 25 °C
Yield: 104.2 %

Procedure:
cis-4-Benzyloxycarbonylamino-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic acid ethyl ester (Example 2) (500 mg), 10% palladium on carbon (150 mg), and a mixture of ethanol-cyclohexene (1:1, 50 mL) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. Purification by silica gel chromatography using 5% methanol/ethyl acetate afforded the title compound (350 mg). MS m/z 258 (M+-16); 1H NMR (CDCl3) δ1.1 (d, 3H), 1.3 (t, 3H), 2.1 (m, 2H), 2.4 (m, 1H), 4.2 (m, 2H), 4.5 (m, 1H), 3.8 (dd, 1H), 7.2 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2[nH]ccc12
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13.02 mmol) was dissolved in 20 mL dimethylformamide. N-Bromosuccinimide (2.55 g, 14.33 mmol) was added under argon atmosphere. The reaction was stirred at room temperature overnight. The crude was poured into water and the precipitate formed was filtered and washed with water. The yellow solid obtained was dried in the vacuum oven to give 2.77 g (91.5% yield) of the title compound. Purity 99%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:37])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)[CH3:18].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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>[CH2:17]([O:19][C:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)=[O:37])[CH3:18]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(=O)O)cc2)cc1

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (2.0 g, 7.07 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (2.46 g, 8.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.80 g, 0.70 mmol), and sodium bicarbonate (4.3 g, 52 mmol) were combined in 1,4-dioxane (50 mL) and water (10 mL), and the reaction was stirred overnight at 80° C. to give the title compound.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C@@H:28]([NH2:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1.CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C@@H:28]([NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH3:29])[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc([C@H](C)N)c1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc([C@H](C)NC2=NC(=O)/C(=C/c3ccc4ncccc4c3)S2)c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(S)-(3-methoxy-phenyl)-ethylamine and DIEA to give 2-[(S)-1-(3-methoxy-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:43]([CH:40]2[CH2:42][CH2:41]2)=[O:44])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)C1CC1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure D using cyclopropanecarbonyl chloride. The final product was obtained in 48% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[O:18][C:19]1[C:20]([F:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>CN(C=O)C>[F:29][C:20]1[C:19]([O:18][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:37]4[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[C:23]([CH3:28])[NH:24]2
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCBr
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 22.6 %

Procedure:
A solution of 6-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline (0.3 g, 0.652 mmol) and 1-(methylsulphonyl)piperazine (0.322 g, 1.95 mmol), (prepared as described for the starting material in Example 2), in DMF (4 ml) was stirred at 80° C. for 2.5 hours. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the resulting solid was filtered, washed with diethyl ether and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline (0.08 g, 23%).
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[CH3:54][C:55]1[O:56][CH:57]=[C:58]([C:60](Cl)=[O:61])[N:59]=1>>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:53])=[O:2])=[O:22])[N:24]([C:60]([C:58]5[N:59]=[C:55]([CH3:54])[O:56][CH:57]=5)=[O:61])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: Cc1nc(C(=O)Cl)co1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)co1

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (30 mg) was reacted with 2-methyl-oxazole-4-carbonyl chloride (prepared above) according to General Procedure F and purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (10 mg). LCMS (m/z): 848.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:10]([N:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCN(Cc1ccccc1)Cc1ccccc1
Yield: 91.2 %

Procedure:
Heat a solution of methyl 4-aminobutanoate hydrochloride (11 g, 71.9 mmol), benzylbromide (25.2 g, 147.3 mmol) and K2CO3 (21.8 g, 158.2 mmol) in MeCN (200 mL) at 40° C. overnight. Concentrate the mixture to dryness, pour the residue into water, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to give the title compound (19.5 g, 91%). 1H NMR (400 MHz, DMSO-d6): δ 7.33-7.18 (m, 10H), 3.57 (s, 3H), 3.52 (s, 4H), 2.43-2.28 (m, 4H), 1.83-1.76 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[C:8]3[S:14][CH2:13][CH2:12][N:9]3[C:10](=O)[C:5]=2[CH:4]=[N:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]2[N:7]=[C:8]3[S:14][CH2:13][CH2:12][N:9]3[C:10](=[S:24])[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c(=O)n3c(nc21)SCC3
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1ncc2c(=S)n3c(nc21)SCC3
Yield: 84.7 %

Procedure:
In 50 ml of toluene was dissolved 2.08 g (10.0 mmol) of Compound 2 prepared in Example 2, and 4.45 g (11.0 mmol) of Lawesson's reagent was added to the solution, followed by heating under reflux for 30 minutes. After cooling, the precipitated crystals were collected by filtration, and then washed with toluene. The crystals were subjected to silica gel column chromatography and eluted with chloroform to give 1.90 g (85%) of Compound 39. The compound was recrystallized from chloroform/ethanol for purification.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(OCC)C>[O:4]=[C:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1ccccc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of diethyl oxalate (11.15 mL, 82.1 mmol) in diethyl ether (50 mL) at −78° C. was treated dropwise with 1 M benzylmagnesium chloride in diethyl ether (82 mL, 82 mmol) while maintaining an internal temperature of −60° C. The mixture was stirred for 30 minutes and poured into a mixture of concentrated HCl (8 mL), ice (40 mL), and diethyl ether (50 mL). The organic phase was washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 15.5 g (98%) of the desired product of sufficient purity for subsequent use.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([O:32]CC)=[O:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([OH:32])=[O:31])=[O:22])=[CH:36][CH:37]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C(=O)O)cc2)cc1
Yield: 92.3 %

Procedure:
A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-ethoxycarbonylphenyl)benzamide (500 mg) in a mixture of ethanol (20 ml) and 1N sodium hydroxide (2 ml) was heated at reflux for 4 hours and ethanol was evaporated in vacuo. Water (5 ml) was added to the residue and the aqueous solution was adjusted to pH 2 with 1N hydrochloric acid. The precipitate was filtered to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-carboxyphenyl)benzamide (435 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[C@@H:19]([NH:21][S:22]([CH:25]4[CH2:27][CH2:26]4)(=[O:24])=[O:23])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:28]4[CH:29]=[CH:30][C:31]([S:34]([CH3:35])=[O:44])=[CH:32][CH:33]=4)[C@@H:19]([NH:21][S:22]([CH:25]4[CH2:26][CH2:27]4)(=[O:24])=[O:23])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NS(=O)(=O)C2CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@H](NS(=O)(=O)C1CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(S(C)=O)cc1
Reaction time: 0.5 h

Procedure:
N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-methylsulfanylphenyl)propan-2-yl]cyclopropanesulfonamide (29, 20.5 mg, 0.04 mmol) was dissolved in DCM (2 mL) and cooled in an ice bath. 3-Chloroperbenzoic acid (70-75%) (10 mg, 0.04 mmol) dissolved in DCM (0.1 mL) was added. The reaction was stirred for 30 min, quenched by addition of 10% Na2SO3 solution (0.5 mL). Purification by HPLC and freeze drying of fractions with product gave the title compound as a colourless solid. Yield 17 mg (80%).
Reaction SMILES: [H-].[Na+].[N:3]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N+:4]=[N-:5].[CH3:19]I>C1COCC1>[N:3]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[N+:4]=[N-:5]
Reactant: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCOCCN=[N+]=[N-])C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
Sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) was placed in a round bottom flask and washed with hexanes (3×) under N2. The dried sodium hydride was treated with 800 mL of anhydrous THF. A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (41.9 g, 182 mmol) in 200 mL of THF was then added to the stirred sodium hydride solution over 40 min. After addition was complete, the reaction was stirred an additional 20 min followed by addition of methyl iodide (13.6 mL, 218 mmol). After stirring overnight, the reaction was quenched with 300 mL of saturated NaHCO3 solution. The reaction mixture was then treated with 200 mL of H2O and 1 L of Et2O. The organic phase was separated and washed with H2O and brine. The organic portion was then dried over MgSO4 and concentrated under reduced pressure to give 41.9 g of tert-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH:15]C(=O)OC(C)(C)C)[CH2:6]1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH2:15])[CH2:6]1.[C:30]([OH:32])([C:29]([F:34])([F:33])[F:28])=[O:31]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccc(F)cc2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1Cc2ccccc2N(Cc2ccc(F)cc2F)C1

Procedure:
tert-butyl 1-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (365 mg) in trifluoroacetic acid and dichloromethane (1:4, v/v) was stirred at room temperature for 3 hours. After removing all the volatiles, toluene (5 mL) was added to the residue and evaporated again. The residue was then dried over vacuum overnight to give 1-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-amine as its TFA salt.