Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:28]([OH:30])=O)=[CH:23][CH:22]=2)=[O:18].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.Cl.CN(C)CCCN=C=NCC>O.O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:31]([C:34]2[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=2)(=[O:33])=[O:32])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:28]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:30])=[CH:23][CH:22]=2)=[O:18]
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3cc(C(=O)O)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3cc(C(=O)N4CCOCC4)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazole-4-carbonyl]-1-(toluene-4-sulfonyl)-1H-indole-5-carboxylic acid (113 mg) was dissolved in water (5 ml) and tetrahydrofuran (THF) (10 ml), and then morpholine (53.5 μl) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (WSC-HCl) (43 mg) were added thereto. The mixture was stirred at room temperature for 24 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol/dichloromethane=0/100 to 17/100) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[5-(morpholine-4-carbonyl)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (59 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[CH3:30][C:31]([CH3:35])([CH3:34])[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NCC(C)(C)C)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 97.1 %

Procedure:
To a solution of (3R)-3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropionamide (0.5 g, 1.3 mmol) and trimethylacetaldehyde (0.26 mL, 2.3 mmol) in 1,2-dichloroethane (10 mL), was added sodium triacetoxyborohydride (0.53 g, 2.5 mmol) at room temperature. After 1 day, the mixture was extracted with methylene chloride (50 mL) and water (20 mL). The organic layer was washed with sodium hydrogen carbonate (sat, 25 mL) and brine (25 mL), and dried over MgSO4. Removal of solvent gave a yellow oil, which was purified by prep HPLC to give (3R)-3-[7-(2,2-dimethyl-propylamino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethyl-propionamide as a white solid (0.59 g, 99% yield): mp 111-113° C.; 1H NMR (CDCl3) δ 1.01 (s, 9H, 3 CH3), 1.43 (t, J=7 Hz, 3H, CH3), 2.89 (s, 3H, CH3), 2.98 (d, J=6 Hz, 2H, CH2), 3.07 (dd, J=6, 15 Hz, 1H, CHH), 3.11 (s, 3H, CH3), 3.45 (dd, J=9, 15 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.12 (d, J=16 Hz, 1H, CHH), 4.33 (d, J=16 Hz, 1H, CHH), 5.59 (dd, J=7, 9 Hz, 1H, NCH), 6.47-6.51 (m, 2H, Ar), 6.79-7.01 (m, 4H, NH, Ar), 7.22 (t, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.75, 27.63, 32, 27, 35.52, 36.67, 37.54, 48.56, 53.10, 54.49, 55.95, 64.42, 107.82, 108.77, 111.25, 112.66, 114.58, 119.22, 132.35, 132.96, 143.09, 148.16, 148.41, 148.81, 169.97, 170.79. Analy. calculated for C27H37N3O4: C, 69.35; H, 7.98; N, 8.99. Found: C, 69.70; H, 7.95; N, 8.74.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:32])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][CH2:43][NH:44][S:45](ON1C(=O)CCC1=O)(=[O:47])=[O:46]>C(#N)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:32])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:45]([NH:44][CH2:43][CH2:42][O:41][CH3:40])(=[O:47])=[O:46])[CH2:13][CH2:12]1
Reactant: COCCNS(=O)(=O)ON1C(=O)CCC1=O
Reactant: O=C(CC1(c2ccc(-c3ccc(Cl)cc3)s2)CCNCCS1(=O)=O)NOC1CCCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCNS(=O)(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(-c3ccc(Cl)cc3)s2)S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-chlorophenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (100 mg) and triethylamine (22.3 mg) in acetonitrile (2 ml) was added N-(2-methoxyethylaminosulfonyloxy)succinimide (55.6 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned with ethyl acetate and water. The organic layer was separated, washed with 5% citric acid solution, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (200:1, 100:1, 200:3) to give N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-(4-chlorophenyl)-2-thienyl)-4-(2-methoxyethylaminosulfonyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (80.0 mg) as a colorless amorphous powder.
Reaction SMILES: F[C:2]1[CH:10]=[C:9](F)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([OH:15])=[O:14].[F:16]C1C=C(F)C=C2C=1CCC2(CC(O)=O)O>>[F:16][C:10]1[CH:2]=[C:3]2[C:7](=[CH:8][CH:9]=1)/[C:6](=[CH:12]/[C:13]([OH:15])=[O:14])/[CH2:5][CH2:4]2
Reactant: O=C(O)CC1(O)CCc2c(F)cc(F)cc21
Reactant: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Product: O=C(O)/C=C1\CCc2cc(F)ccc21
Yield: 68 %

Procedure:
This compound was prepared in an analogous manner to (E)-2-(4,6-difluoro-1-indanylidene)acetic acid in Example 5e by substituting 2-(5-fluoro-1-hydroxy-1-indanyl)acetic acid (14.70 g, 0.069 mol) for 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid. Recrystallization from acetonitrile:2-propanol mixtures gave 9.05 g (68%) of (E)-2-(5-fluoro-1-indanylidene)acetic acid as a white solid: m.p., 240-242° C.;
Reaction SMILES: F[B-](F)(F)F.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=2[F:29])[C:16]([NH2:18])=[S:17])=[CH:10][CH:9]=1)#[N:7].[C:30](OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:30][S:17][C:16](=[NH:18])[CH:15]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=1)[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=1[F:29]
Reactant: CCOC(C)=O
Reactant: COc1cc(OC)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(OC)c(F)c(C(Nc2ccc(C#N)cc2)C(=N)SC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
After adding 0.904 g of Me3O+BF4− to a solution of 2.01 g of 2-(4-cyanophenylamino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetamide in 150 ml of acetonitrile under a nitrogen atmosphere, the mixture was stirred at room temperature for 5 hours. Next, 400 ml of ethyl acetate and 300 ml of saturated aqueous sodium hydrogencarbonate were added and the organic layer was washed with 300 ml of water and 300 ml of saturated brine. The mixture was dried over anhydrous magnesium sulfate and the desiccating agent was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (2.05 g) as a light yellow solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:21]([CH3:30])[N:22]=CC1C=CC=CC=1)[NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]2OCCO2)[CH:11]=1)#[N:2].Cl.[NH:32]1[CH2:37][CH:36]=[CH:35][CH2:34][CH2:33]1.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:30][N:21]1[C:4]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:32]3[CH2:33][CH:34]=[CH:35][CH2:36][CH2:37]3)[CH:11]=2)=[N:3][C:1]([NH2:2])=[N:22]1
Reactant: CN(N=Cc1ccccc1)C(=NC#N)NCCCOc1cccc(C2OCCO2)c1
Reactant: C1=CCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CC=CCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N'-cyano-N-[3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl]-1-methyl-2-(phenylmethylene) hydrazinecarboximidamide (2.62 g) in tetrahydrofuran (40 ml) was stirred at room temperature for 0.5 h with 2 N hydrochloric acid (5 ml). The mixture was treated with 1,2,3,6-tetrahydropyridine (9 ml) and stirred at room temperature for a further 1 h. The mixture was treated with sodium borohydride (1.5 g), stirred at room temperature for 18 h, diluted with ethyl acetate, filtered and the filtrate evaporated in vacuo. The resulting oil was partitioned between ethyl acetate and water. The organic phase was evaporated in vacuo and the residue was purified by column chromatography on silica, using methanol. Evaporation of the eluates gave the title compound which was recrystallised from a mixture of benzene and cyclohexane (1.26 g) m.p. 102°-3°. TLC silica; methanol-ammonia 80:1; Rf 0.6.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28](C)([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:13][C:12]2=[O:32])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(C1C=CC(N2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC2=O)=CC=1)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][CH:28]([CH3:29])[CH3:30])=[O:26])[CH2:23][CH2:24]3)=[CH:13][C:12]2=[O:32])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1

Procedure:
Example 5 was prepared according to procedures described in Example 3 substituting tert-butyl 4-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)methyl)piperidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=8.25 Hz, 2H), 7.61 (d, J=8.80 Hz, 2H), 7.23 (d, J=7.70 Hz, 1 H), 6.09 (dd, J=7.70, 2.75 Hz, 1H), 6.01 (d, J=2.75 Hz, 1H), 4.87-4.98 (m, 1H), 4.23 (app brs, 2H), 3.85 (d, J=6.05 Hz, 2H), 3.09 (s, 3H), 2.79 (t, J=2.65 Hz, 2H), 1.87-2.06 (m, 1H), 1.76-1.87 (d, J=12.10 Hz, 2H), 1.18-1.37 (m, 6H), 1.25 (d, J=6.05 Hz, 6H). MS (ESI) 449 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([NH:16][NH2:17])=[O:12])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CNc1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)CNc1ccc(Cl)cc1
Yield: 58.4 %

Procedure:
Ethyl 2-(4-chlorophenylamino)acetate (A) (25.6 g, 120 mmol) and hydrazine monohydrate (7.0 mL, 144 mmol) were heated to reflux in ethanol (120 mL) for 22 hours. After concentration in vacuo, the solid obtained was recrystallised from ethanol to yield the title compound (14.0 g, 59%) as a pale brown powder. 1H NMR (400 MHz, CDCl3) δ 3.85 (2H, d), 4.18 (2H, br), 6.53 (2H, d), 7.16 (2H, d), 7.60 (1H, br).
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C:34](C)([CH3:36])[CH3:35])[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](O)(=[O:41])C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C@H:34]1[CH2:36][CH2:39][O:41][CH2:35]1)[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
tert-butyl N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was dissolved in a 1:1 solution of CH2Cl2/TFA (1 mL) and allowed to stir at room temperature for 1 hour. The solution was then extracted into ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated to a clear oil. The resulting oil was then dissolved in THF (1 mL) and combined with 2,5-dioxo-1-pyrrolidinyl [(3S)tetrahydro-3-furanyl]carbonate (0.05 mmol, 13 mg) DIEA (0.08 mmol, 14 gL) and allowed to stir for 15 hours. The reaction was neutralized by the addition of acetic acid and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a white solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate), providing 19 mg (37%) of a white solid. H1-NMR (CDCl3): δ7.70 (2H,d), 7.29-7.17 (6H,m), 6.97 (2H,d), 5.1 (1H,s), 4.76 (1H,d), 4.17 (1H,m), 3.86 (3H,s), 3.87-3.70 (6H,m), 3.68-3.60 (1H,m), 3.06 (1H,bs), 2.89 (2H,m), 2.02 (3H,m), 1.89 (1H,m), 1.71 (2H,m),1.28-1.08 (6H,m); MS (ESI): M+Na=585.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].N1C=CC=CC=1.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>C1COCC1>[CH3:2][O:3][N:4]([CH3:5])[C:12](=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)N(C)OC
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
O,N-dimethylhydroxylamine hydrochloride (74.6 g, 765 mmol) was dissolved in THF (1 L) and pyridine (123 ml, 1531 mmol) was added and stirred for 30 min. Methacryloyl chloride (37.4 ml, 383 mmol) was added slowly and stirred overnight. The solids were filtered and concentrated. The residue was partitioned between water and CH2Cl2, washed with water, dried over sodium sulfate, filtered and concentrated to afford N-methoxy-N-methylmethacrylamide (56.5 g, 335 mmol, 87.5% yield).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[OH:34])[N:17]=2)[CH2:12]1.Cl[C:36]([O:38][C@H:39]1[CH2:43][CH2:42][O:41][CH2:40]1)=[O:37]>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][C@@H:11]([NH:10][C:36](=[O:37])[O:38][C@H:39]3[CH2:43][CH2:42][O:41][CH2:40]3)[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=1
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)O[C@H]4CCOC4)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
At room temperature, N-ethyl-N-isopropylpropan-2-amine (155 mL, 0.88 mmol) was added to a solution of 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (150 mg, 0.40 mmol) in THF. The mixture was cooled in an ice bath, and (S)-tetrahydrofuran-3-yl chloroformate (63 mg, 0.42 mmol) was added slowly over a period of 10 minutes. After warming to room temperature, the reaction was quenched with water and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in CH2Cl2/hexanes (1:1) gave (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (160 mg, 84%). LC/MS: m/z 453.3 (M+H)+ at 2.12 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSOd6) δ 8.18 (d, J=8.6 Hz, 1H), 7.70 (d, J=6.3 Hz, 1H), 7.58 (s, 1H), 7.29-7.38 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.67-6.72 (m, 1H), 5.14 (s, 1H), 4.23-4.24 (m, 1H), 3.99-4.13 (m, 3H), 3.64-3.85 (m, 5H), 2.50 (s, 3H), 2.07-2.22 (m, 2H), 2.00-2.03 (m, 1H), 1.85-1.90 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[CH:17][C:16]([C:27](O)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[CH:17][C:16]([C:27]([NH2:38])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(C(N)=O)ccc2c1=O
Yield: 69.3 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.17 g, 2.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.96 g, 5 mol) and 1-hydroxybenzotriazole ammonium salt (0.76 g, 5 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (0.81 g, 69.8%) as crystals.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][NH:6][C:7]1[S:8][C:9]([SH:12])=[N:10][N:11]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH3:5][NH:6][C:7]1[S:8][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][N:11]=1
Reactant: BrCc1ccccc1
Reactant: CNc1nnc(S)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CNc1nnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
To a solution of sodium ethoxide in ethanol (prepared by adding 13.5 g of anhydrous sodium methoxide to 300 ml of absolute ethanol) was added 31 g of 2-methylamino-5-mercapto-1,3,4-thiadiazole. After stirring for 15 min. at room temperature, 36 g of benzyl bromide was added to the homogeneous solution and the reaction heated to reflux for 4 hrs. At the end of the reflux period, most of the ethanol was removed at reduced pressure, water was added and the reaction extracted with ethyl acetate, which was washed with water and saturated NaCl, then dried over Na2SO4. Removal of the solvent gave a viscous oil which was crystallized from a mixture of ether and petroleum ether to give 29.7 g of 2-methylamino-5-benzylthio-1,3,4-thiadiazole, MP 87-891/4C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:49]=[C:50]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:51]=1)[CH2:10][N:11]([CH:46]1[CH2:48][CH2:47]1)[C:12]([C@@H:14]1[C@@H:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=3[Cl:38])=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:15]1)=[O:13])#[N:2].C([Sn]([N:70]=[N+:71]=[N-:72])(CCCC)CCCC)CCC>O1CCOCC1.CCOC(C)=O>[CH:46]1([N:11]([CH2:10][C:9]2[CH:8]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][C:1]3[N:70]=[N:71][NH:72][N:2]=3)[CH:51]=[C:50]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:49]=2)[C:12]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:18][CH2:17][N:16]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:15]2)=[O:13])[CH2:48][CH2:47]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCC#N)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCc2nn[nH]n2)c1
Temperature: 150 °C

Procedure:
To a solution of tert-butyl (3R,4S)-3-{[[3-(3-cyanopropoxy)-5-(3-methoxy-propyl)benzyl](cyclopropyl)amino]carbonyl}-4-{4-[2-(2,6-dichloro-4-methylphen-oxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in dioxane (0.17 M) was added tri-n-butyltin azide (3 eq.). The reaction was heated to 150° C. in a sealed tube for 18 h. After cooling down to rt, the reaction was diluted with EtOAc. The organic extract was washed with saturated aqueous NH4Cl solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, first 50% EtOAc in Hex to 100% EtOAc, then 5% MeOH in DCM) to afford the title compound as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([O:53][C:54]([N:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57]1[C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([NH2:71])[CH:66]=1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C>[C:49]([O:53][C:54]([N:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57]1[C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([NH:71][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:66]=1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc2ccccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-indole-1-carboxylic acid tert-butyl ester (0.02 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.02 g of product in 64% yield: LCMS (ESI) m/z 497 (MH+).