Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][S:9]([NH:12][C:13]1[C:14]([CH3:38])=[C:15]2[C:19](=[C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]=1[CH3:22])[N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16]2)(=[O:11])=[O:10])=O)(C)(C)C.[ClH:39].CC(O)C.C(OCC)C>C(O)=O>[ClH:39].[CH3:38][C:14]1[C:13]([NH:12][S:9](=[O:10])(=[O:11])[NH2:8])=[C:21]([CH3:22])[C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])=[C:19]2[C:15]=1[CH2:16][CH2:17][N:18]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCN1CCc2c(C)c(NS(=O)(=O)NC(=O)OC(C)(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Agent: Cl
Solvent: O=CO
Solvent: CCOCC
Solvent: CC(C)O
Product: CCCCCCCCN1CCc2c(C)c(NS(N)(=O)=O)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 0.33 h

Procedure:
The compound (1.86 g) obtained in Example 5 was dissolved in formic acid (7.5 mL) and 8.51 M hydrogen chloride—2-propanol solution (1.98 mL) was added under ice-cooling. The mixture was stirred at the same temperature for 20 min. Diethyl ether (50 mL) was added, and the precipitated crystals were collected by filtration to give the title compound as crystals (1.34 g).
Reaction SMILES: [Na].[CH2:2]([SH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([C:15]1[CH:16]=[C:17]([CH:37]=[C:38]([CH3:41])[C:39]=1[OH:40])[NH:18][C:19]1[N:24]=[C:23]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:22]=[C:21](Cl)[N:20]=1)([CH3:14])([CH3:13])[CH3:12]>CO>[C:11]([C:15]1[CH:16]=[C:17]([CH:37]=[C:38]([CH3:41])[C:39]=1[OH:40])[NH:18][C:19]1[N:24]=[C:23]([NH:25][CH:26]2[CH2:31][C:30]([CH3:32])([CH3:33])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:22]=[C:21]([S:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[N:20]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCCCCCCS
Reactant: Cc1cc(Nc2nc(Cl)nc(NC3CC(C)(C)NC(C)(C)C3)n2)cc(C(C)(C)C)c1O
Agent: [Na]
Solvent: CO
Product: CCCCCCCCSc1nc(Nc2cc(C)c(O)c(C(C)(C)C)c2)nc(NC2CC(C)(C)NC(C)(C)C2)n1
Temperature: 0 °C

Procedure:
1.15 g of sodium were dissolved in 150 ml of methanol and 7.3 g of n-octylmercaptan were added. A solution of 10.8 g of 2-(3-tert.-butyl-5-methyl-4-hydroxyanilino)-4-[(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-6-chloro-1,3,5-triazine in 200 ml of methanol was added to the resulting sodium n-octylmercaptide, whilst stirring. The reaction mixture was kept under reflux for 16 hours and then poured into 400 ml of ice water, a slightly brownish precipitate, which was filtered off, being formed. Recrystallization from ethyl acetate/hexane gives 13.9 g of almost colourless 2-(3-tert.-butyl-5-methyl-4-hydroxyanilino)-4-[(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-6-(n-octylthio)-1,3,5-triazine having a melting point of 133° C. (stabiliser 2).
Reaction SMILES: BrBr.[C:3]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C@@H:21]1[C:16](=[CH:17][C:18](=[O:25])[CH2:19][CH2:20]1)[CH2:15][C@H:14]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:5])[CH3:4].O>C(O)(=O)C.C(OCC)C>[C:3]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH:15]=[C:14]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:5])[CH3:4]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCCCCCCC(=O)O)CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Agent: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C(CCCCCCCCCCC(=O)O)=Cc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (0.114 ml.) in acetic acid (2 ml.) was added dropwise to a stirred solution of 11-(17β-acetoxy-3-oxo-oestra-4-en-7α-yl)undecanoic acid (Example 2; 0.5 g.) in a mixture of diethyl ether (5 ml.) and acetic acid (2 ml.) which was cooled to 15° C. and the mixture was stirred at that temperature for 30 minutes and then poured into water (50 ml.). The mixture was extracted three times with methylene chloride (30 ml. each time) and the combined extracts were washed with water, dried and rapidly evaporated to dryness under reduced pressure at a bath temperature below 20° C. A solution of the residue, which consisted of 11-(17β-acetoxy-2,6-dibromo-3-oxooestr-4-en-7α-yl)undecanoic acid in dimethylformamide (3 ml.) was immediately added to a stirred mixture of lithium bromide (1.0 g.), lithium carbonate (1.0 g.) and dimethylformamide (10 ml.) which was heated under reflux, and the mixture was stirred and heated under reflux for 30 minutes and then evaporated to dryness under reduced pressure. Water (20 ml.) was added to the residue and the mixture was acidified to pH 1 with aqueous N-hydrochloric acid and extracted three times with methylene chloride (20 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 7:3 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 11-(17β-acetoxy-3-hydroxyoestra-1,3,5(10),6-tetraen-7-yl)undecanoic acid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[C@@H:12]([NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].FC(F)(F)S(O[CH2:31][CH:32]([F:34])[F:33])(=O)=O>CN(C=O)C.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:31][CH:32]([F:34])[F:33])[C@@H:12]([NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OCC(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
30.1 A suspension of 37 mg NaH (55% in oil) in 2 ml DMF was treated at 0° C. under an argon atmosphere with a solution of 270 mg (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.4). The reaction mixture was stirred for 1 hr at r.t. Then, 334 mg 2,2-difluoroethyl trifluoromethanesulfonate were added at 0° C. The reaction mixture was stirred for 2 days at r.t., then diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was isolated by chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 9:1) to give 157 mg (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-(2,2-difluoro-ethoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester. Colorless solid. MS 409.0 ([M+H]+)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.B(O)(O)[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[S:35][CH:34]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[S:35]1[CH:34]=[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=3)[NH:4][N:3]=2)[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3csc4ccccc34)c2c1
Yield: 35.8 %

Procedure:
N-(3-Benzo[b]thiophen-3-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 300 mg thianaphthene-3-boronic acid, 20 ml of dimethylformamide, 1.9 ml of saturated aqueous solution of sodium hydrogencarbonate and 25 mg of tetrakis(triphenylphosphine)palladium[0]. 150 mg of N-(3-benzo[b]thiophen-3-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 235° C. (analysis C22H17N3O4S3% calculated C, 54.64; H, 3.54; N, 8.69; O, 13.23; S, 19.89. % found C, 54.35; H, 3.68; N, 8.68; S, 20.12).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(C(OCC2C=CC=CC=2)=O)[C:10](=[O:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:10](=[O:30])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1(C(=O)OCc2ccccc2)CCN(Cc2ccccc2)CC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCN(Cc2ccccc2)CC1=O

Procedure:
A mixture of benzyl 1-benzyl-4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-4-carboxylate (18.5 g, 45.2 mmol) and 10% palladium-on-carbon (1.5 g) in EtOAc (50 ml) is treated with 15 psi of hydrogen for 2 hours. The reaction mixture is filtered through a celite pad, washing with EtOAc (100 ml). The combined filtrate is concentrated in vacuo to afford the title compound.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]=[C:29]=[S:30])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][NH:28][C:29]([NH2:1])=[S:30])[CH2:24][CH2:25]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: N
Solvent: CO
Product: NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
A mixture of 120 parts of methanol saturated with ammonia and 4.1 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine was stirred overnight at room temperature. The reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 1,1'-oxybisethane. The product was filtered off and crystallized from acetonitrile, yielding 1.1 parts (26%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea; mp. 186.1° C. (intermediate 149).
Reaction SMILES: Cl.C([O:9][C:10]1[C:15](=[O:16])[CH:14]=[CH:13][N:12]([CH2:17][CH2:18][OH:19])[C:11]=1[CH:20]([OH:28])[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)C1C=CC=CC=1.[OH-].[Na+]>C(OCC)(=O)C>[Br:27][C:24]1[CH:23]=[CH:22][C:21]([CH:20]([OH:28])[C:11]2[N:12]([CH2:17][CH2:18][OH:19])[CH:13]=[CH:14][C:15](=[O:16])[C:10]=2[OH:9])=[CH:26][CH:25]=1
Reactant: O=c1ccn(CCO)c(C(O)c2ccc(Br)cc2)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=c1ccn(CCO)c(C(O)c2ccc(Br)cc2)c1O
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
12 ml of 37% conc. HCl are poured over 1.2 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-[hydroxy-(4-bromo-phenyl)-methyl]-1H-pyridin-4-one and the reaction mixture is heated with stirring at 110° C. for 10 minutes. After cooling, 15 g of ice are added. With stirring and cooling in an ice bath, the reaction mixture is neutralised with sodium hydroxide solution to a pH of 6.5. 15 ml of ethyl acetate are added and stirring is carried out at room temperature for 18 hours. The resulting product is filtered off and washed with water and ethyl acetate. Recrystallisation from ethanol yields 2-[(4-bromo-phenyl)-hydroxy-methyl]-3-hydroxy-1-(2-hydroxy-ethyl)-1H-pyridin-4-one.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[O:12][CH3:13].C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)CCC>CN(C)C=O.[Cu]=O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1cc2ccncc2cc1Br
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: COc1cc2ccncc2cc1-c1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
7-Bromo-6-methoxyisoquinoline (200 mg), tetrakistriphenylphosphine palladium(0) (97 mg), and copper(II) oxide (134 mg) were suspended in N,N-dimethylformamide (5 ml), tri-n-butyl-(2-pyridyl)-tin (618 mg) was added to the suspension, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature, the reaction solution was then fitlered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 6-methoxy-7-pyridin-2-yl-isoquinoline (122 mg, yield 62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][C:8](=[O:12])SCC)[C:4](=[O:13])[O:3]1.C([SiH](CC)CC)C>C(Cl)Cl.[Pd]>[CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][CH:8]=[O:12])[C:4](=[O:13])[O:3]1
Reactant: CCSC(=O)C[C@H]1OC(C)(C)OC1=O
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@@H](CC=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
(R)—S-Ethyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (22.5 g, 103 mmol) was dissolved in CH2Cl2 (500 mL), purged with nitrogen and 10% palladium on carbon (2.19 g, 2.06 mmol) was added and triethylsilane (24.7 mL, 155 mmol) was dissolved in CH2Cl2 (20 mL) and added dropwise through an addition funnel over 30 minutes and stirred at ambient temperature overnight under nitrogen. The reaction was filtered through celite, concentrated and purified over silica gel (10 to 40% EtOAc in hexanes) to afford (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (16 g, 101 mmol, 98.1% yield) as a clear colorless oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([C:28]1[C:33]2[N:34]([CH2:37][C:38]([OH:40])=O)[CH:35]=[N:36][C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:27])[CH3:26].[NH2:41][CH:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]([CH3:54])([CH3:53])[C:51]#[N:52])=[C:46]([F:55])[CH:45]=1)[CH3:43].CCN(CC)CC>CC#N.O>[C:25]([C:28]1[C:33]2[N:34]([CH2:37][C:38]([NH:41][CH:42]([C:44]3[CH:49]=[CH:48][C:47]([C:50]([C:51]#[N:52])([CH3:54])[CH3:53])=[C:46]([F:55])[CH:45]=3)[CH3:43])=[O:40])[CH:35]=[N:36][C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(F)c1
Reactant: CC(=O)c1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(=O)c1cccc2ncn(CC(=O)NC(C)c3ccc(C(C)(C)C#N)c(F)c3)c12

Procedure:
2-(7-Acetyl-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-fluorophenyl]ethyl}acetamide is synthesized according to example 5 by mixing HATU (179 mg, 0.472 mmol), 7-acetyl-1H-benzimidazol-1-ylacetic acid (103 mg, 0.472 mmol) prepared according to scheme 4, 2-[4-(1-aminoethyl)-2-fluorophenyl]-2-methylpropanenitrile (97.0 mg, 0.472 mmol) prepared according to scheme 7 and Et3N (143 mg, 1.42 mmol, 0.200 mL) in dry MeCN (10.0 mL). The product is purified by reverse phase HPLC: Gilson prep pumps; Flow rate: 30 ml/min; Column: Gemini (50 21.2×50 mm; Mobile phase: A=10.0 mM NH4HCO3 in H2O B=MeCN (52.4 mg, 0.129 mmol, 27.0%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.36 (d, J=7.03 Hz, 3H) 1.70 (s, 6H) 2.40 (s, 3H) 4.72-4.90 (m, 1H) 5.17 (dd, J=21.48, 17.19 Hz, 2H) 7.18 (d, J=7.81 Hz, 1H) 7.21-7.32 (m, 2H) 7.40 (t, J=8.30 Hz, 1H) 7.72 (d, J=7.62 Hz, 1H) 7.86 (d, J=7.81 Hz, 1H) 8.22 (s, 1H) 8.72 (d, J=7.42 Hz, 1H); MS [M+H] calcd.: 407.18. found: 407.17.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]2)[C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[CH2:32][N:33](C(C)C)[CH:34](C)C.Cl.CNC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]2)[C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:13][C@H:9]1[C:10]([N:33]([CH3:34])[CH3:32])=[O:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of (4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-L-proline (0.93 g, 2.2 mmol) prepared in Step C in DMF (10□) was added dropwise DIPEA (0.95□, 5.5 mmol) followed by dimethylamine-HCl salt (0.21 g, 2.57 mmol) and HBTU (0.83 g, 2.2 mmol). The reaction solution was stirred at rt for 2 h, and concentrated in vacuo. The residue was diluted with EtOAc, washed with a saturated NaHCO3 aqueous solution, water and 1N HCl. The organic solution was dried over MgSO4, concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc:Hex=2/1) to give the title compound (0.92 g, 93%).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[CH3:25][N:26]([CH3:43])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]#[C:36][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[OH:34])=[CH:29][CH:28]=1.CN(C)C1C=CC(C(C#C)O)=CC=1>C(OCC)C>[CH3:43][N:26]([CH3:25])[C:27]1[CH:28]=[CH:29][C:30]([C:33](=[O:34])[C:35]#[C:36][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:31][CH:32]=1
Reactant: CN(C)c1ccc(C(O)C#Cc2ccncc2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: C#CC(O)c1ccc(N(C)C)cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)C#Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place pyridinium dichromate (1.75 g) and methylene chloride (20 mL) under argon atmosphere and cool to 0° C. Add a 1:1 mixture of 4-dimethylamino-α-[(4-pyridinyl)ethynyl]-benzenemethanol and 4-dimethylamino-α-(ethynyl)benzenemethanol (0.8 g). Stir overnight while slowly warming to room temperature. Dilute with ethyl ether and filter the chromium salts. Purify by silica gel chromatography (2:1 ethyl acetate/hexane) to yield 0.94 g of the title compound; mp 143°-145° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[NH2:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:23])([CH3:24])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
A mixture of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (8.7 g, 26.8 mmol) in methanol (80 mL) and tetrahydrofuran (100 mL), 30% sodium hydroxide in water (50 mL) was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (7 g, 88%) as a brown solid which was used for next step without further purification: LC/MS m/e calcd for C18H20N2O2 (M+H)+: 297.37, observed: 297.2.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH:45]=[CH:46][CH:47]=2)[O:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)O1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:46]2[CH:47]=[CH:33][CH:34]=[C:35]([O:36][CH2:37][CH2:38][N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[CH:45]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2cccc(OCCN3CCOCC3)c2)OC1(C)C
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2cccc(OCCN3CCOCC3)c2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 4-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (62 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(3-(2-morpholinoethoxy)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=451).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(OCC)(=O)C>[CH2:27]([O:26][C:24]([NH:1][CH:2]([CH2:3][CH2:4][C:5](=[O:7])[NH2:6])[C:8]([OH:10])=[O:9])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)CCC(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
Glutamine (36.5 g, 0.25 mol) was stirred with 1M sodium bicarbonate (750 ml) and toluene (200 ml). Benzyl chloroformate (50 ml, 59.75 g, 0.35 mol, 1.4 equiv.) was added drop-wise over 20 min. and the resulting mixture was stirred under nitrogen at room temperature overnight. Ethyl acetate (400 ml) was added and phases were separated. The organic phase was extracted with water (50 ml) and discarded. The aqueous phase was acidified with 6N hydrochloric acid and extracted with ethyl acetate (2×600 ml). The combined extracts were washed with water (100 ml) and stripped. The residue was dried in a vacuum oven (50° C.) to produce (1) (64 g, 91.4%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C[Li].Cl.[C:15](=O)([O-])O.[Na+]>O1CCCC1.ClCCl>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: Cc1cccc(C(=O)O)c1Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [Li]C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cccc(C)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-3-methylbenzoic acid (1.71 g, 10.0 mmol) in anhydrous tetrahydrofuran (10 ml), at 0° C. and under nitrogen, was added methyllithium (1.6M in diethyl ether, 13.1 ml, 21.0 mmol), via syringe. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to room temperature over 1 h. To the reaction mixture was added cold hydrochloric acid (1M, 100 ml) and dichloromethane (110 ml). The mixture was adjusted to pH 7 by addition of saturated aqueous sodium hydrogen carbonate solution and the two layers were separated. The aqueous layer was extracted with further dichloromethane and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (1.19 g).