Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)=[CH:8][C:6]=2[CH:7]=1.[CH3:17][O:18][C:19](=[O:31])[C@H:20]([N:28]=[C:29]=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1>[CH3:17][O:18][C:19](=[O:31])[C@H:20]([NH:28][C:29]([O:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)=[CH:8][C:6]=2[CH:7]=1)=[O:30])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Reactant: OCc1cc2cc(-c3ccsc3)ccc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccsc3)ccc2o1
Temperature: 50 °C
Yield: 47.6 %

Procedure:
A mixture of 2-hydroxymethyl-5-thiophen-3-yl-benzofuran 22 (0.31 g, 1.35 mmole), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (0.33 g, 1.6 mmole), triethylamine (0.43 ml), and THF (25 ml) was heated to 50° C. under a nitrogen atmosphere for 14 hrs. The solvent was removed under reduced pressure and the residue was purified by chromatography giving about 0.28 g of (R)-2-(5-thiophen-3-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenylpropionic acid methyl ester 23, mp. 105-106° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH:26](=O)[CH3:27].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH2:26][CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1
Reactant: CC=O
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)OC)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
4-[1-(3-Amino-2-pyridyl)piperazin-4-yl-carbonyl]benzoic acid methyl ester (4 g) was dissolved in methanol (80 ml) and then, acetaldehyde (1.7 ml) and acetic acid (4 ml) were added at 0° C. The solution was stirred at 0° C. for 30 minutes. Then, with the addition of sodium cyanoborohydride (2.2 g), the solution was stirred at 0~5° C. for 2 hours. Excess of water was added gradually, and the solution was neutralized (pH=~8) by addition of aqueous 3N-sodium hydroxide. The mixture was stirred for 1 hour and filtered, and the crude solid was recrystallized using methanol and ether to give 3.51 g (yield: 81%) of the desired compound.
Reaction SMILES: [CH:1]1([CH:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][NH:5]2)[CH2:3][CH2:2]1.C(Cl)(=O)C(C)C.C1(C(Cl)=O)CC1>>[CH:1]([CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)C(C1CC1)NCC2
Agent: CC(C)C(=O)Cl
Agent: O=C(Cl)C1CC1
Product: COc1cc2c(cc1OC)C(C(C)C)NCC2

Procedure:
1,2,3,4-Tetrahydro-1-isopropyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1.2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxy- isoquinoline but substituting in the first step isobutyryl chloride for cyclopropylcarbonyl chloride.
Reaction SMILES: Br[C:2]1[C:3](=[O:22])[CH2:4][CH2:5][C:6]2([CH2:18][CH2:19][CH2:20][CH3:21])[C:14]=1[C:13]1[C:8](=[C:9]([Cl:17])[C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2.[Cu][C:24]#[N:25]>CN1CCCC1=O>[CH2:18]([C:6]12[CH2:5][CH2:4][C:3](=[O:22])[C:2]([C:24]#[N:25])=[C:14]1[C:13]1[C:8](=[C:9]([Cl:17])[C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)c(Cl)c1C2
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCCCC12CCC(=O)C(C#N)=C1c1ccc(OC)c(Cl)c1C2
Temperature: 150 °C
Yield: 73.5 %

Procedure:
A solution of 4-bromo-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (103 mg, 0.268 mmol) in anhydrous 1-methyl-2-pyrrolidinone (0.54 mL) was treated with copper(I) cyanide (24 mg, 0.268 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 150° C. for 1.5 hours. After cooling to room temperature, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (5×50 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil. The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 5% EtOAc in CH2Cl2. The product band was eluted with EtOAc and the eluent evaporated under vacuum to afford 9a-butyl-8-chloro-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (65 mg) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]([CH3:14])[CH2:10][C@H:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]([CH3:22])([CH3:14])[CH2:10][C@H:9]1[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CC(C)(C)C(=O)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-4-methyl-L-pyroglutamate (1.2 g, 4.0 mmol) in tetrahydrofuran (20 mL) stirring at −78° C., was added a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran (4.4 mL, 4.4 mmol) dropwise over 5 minutes. After 30 minutes, methyliodide (0.33 mL, 5.2 mmol) was added. After an additional 3 hours at −78° C., the cooling bath was removed and 50% saturated aqueous ammonium chloride (40 mL) was added. The solution was stirred for 20 minutes, then extracted with ether (2×50 mL). The combined organic layers were washed with water(2×25 mL), saturated sodium bicarbonate (2×25 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated to give Boc-PyroGlu(4,4-dimethyl)-OtBu (0.673 g, 54%). Step 3. Synthesis of tert-butyl N-tert-butoxycarbonyl-4,4-dimethylproline (Boc-Pro(4,4-dimethyl)-OtBu)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1)=[O:4].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[Cl:42]>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][C:39]3[CH:38]=[CH:37][C:36]([Cl:35])=[C:41]([Cl:42])[CH:40]=3)[CH:12]=2)[N:7]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=2)[C:6]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2c(C(=O)OC)c3cc(O)ccc3n2-c2ccc(OC(C)C)cc2)cc1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(-c2c(C(=O)OC)c3cc(Oc4ccc(Cl)c(Cl)c4)ccc3n2-c2ccc(OC(C)C)cc2)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-hydroxy-1-(4-isopropoxyphenyl)-2-(4-methoxycarbonylphenyl)indole-3-carboxylic acid methyl ester (150 mg, 0.32 mmol, see step (b) Example 43) and 3,4-dichlorophenylboronic acid (120 mg, 0.64 mmol). Yield 60 mg (32%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]2[C:7](=[O:29])[N:8]([C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:5]=2[CH:4]=1.[Br:32]CC.[Br-].[Na+]>O.CC(O)C.CN1CCCC1=O>[Br:32][CH2:2][C:3]1[CH:31]=[CH:30][C:6]2[C:7](=[O:29])[N:8]([C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:5]=2[CH:4]=1
Reactant: O=c1c2ccc(CCl)cc2on1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCBr
Agent: [Br-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(C)O
Solvent: O
Product: O=c1c2ccc(CBr)cc2on1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 57.5 °C
Reaction time: 1.5 h

Procedure:
10.0 g of 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one, 35 mL of bromoethane and 2.42 g of sodium bromide were added to 80 mL of N-methyl-2-pyrrolidone, and this was stirred for 1.5 hours at 55-60° C. After cooling the reaction mixture, 20 mL of 2-propanol and 50 mL of water were added dropwise and solids were filtered to obtain a white solid. The obtained white solid, 35 mL of bromoethane and 2.42 g of sodium bromide were added to 80 mL of N-methyl-2-pyrrolidone, and this was stirred for 1 hour at 55-60° C. After cooling the reaction mixture, 20 mL of 2-propanol and 50 mL of water were added dropwise and solids were filtered to obtain 9.04 g of 6-(bromomethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one in the form of a white solid.
Reaction SMILES: BrC1C(C)(C)CC2C(C=1)=CC=C(OC)C=2.BrC1C=CC=CC=1[N+]([O-])=O.[CH3:26][O:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[C:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[N+:46]([O-])=O)[C:34]([CH3:39])([CH3:38])[CH2:35]2)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:37]=[C:36]2[C:31](=[CH:30][CH:29]=1)[CH2:32][CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH2:46])[C:34]([CH3:39])([CH3:38])[CH2:35]2
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccccc1[N+](=O)[O-])=C2
Agent: COc1ccc2c(c1)CC(C)(C)C(Br)=C2
Agent: O=[N+]([O-])c1ccccc1Br
Product: COc1ccc2c(c1)CC(C)(C)C(c1ccccc1N)C2
Yield: 74.4 %

Procedure:
Synthesized from 3-bromo-7-methoxy-2,2-dimethyl-1,2-dihydronaphthalene and 1-bromo-2-nitrobenzene according to an analogous synthetic method to Preparation Example 107 described below, 7-methoxy-2,2-dimethyl-3-(2-nitrophenyl)-1,2-dihydronaphthalene (1.4 g) was used according to an analogous synthetic method to Example 30 to provide the title compound (948 mg).
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]1.Br[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:37][C:33]1[CH:32]=[C:31]([NH:1][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][C:15]([C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[O:19])=[CH:16][CH:17]=4)[CH:10]=3)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]2)[CH:36]=[CH:35][CH:34]=1
Reactant: Clc1cccc(Br)c1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](Nc2cccc(Cl)c2)C[C@@H]1C
Temperature: 120 °C
Yield: 45 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 56) (100 mg, 0.254 mmol), 1-bromo-3-chlorobenzene (0.060 mL, 0.507 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (20.0 mg, 0.051 mmol), tris(dibenzylideneacetone)dipalladium(0) (23.3 mg, 0.025 mmol) and sodium tert-butoxide (34.1 mg, 0.355 mmol) were combined in 1,4-dioxane (2.5 mL). The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120° C. for 25 mins. The mixture was partitioned between water (50 mL) and DCM (3×50 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by MDAP (HpH) to give 1-((2S,4R)-4-((3-chlorophenyl)amino)-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (58 mg, 0.115 mmol, 45% yield).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CO.C(Cl)Cl>[Br:25][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([CH2:7][CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:9][CH2:10][CH2:11]2
Reactant: c1ccc2c(c1)CCCN2CCN1CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: Brc1ccc2c(c1)CCCN2CCN1CCCC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 57.7 %

Procedure:
A solution of 1-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroquinoline (490 mg, 2.13 mmol) in 10 mL of carbontetrachloride was cooled to 0° C. then treated with NBS (378 mg, 2.13 mmol) portionwise. The resulting suspension was stirred at 0° C. for 3.5 hours. The mixture was filtered through celite and the filter pad was rinsed with 3×20 mL hexanes. The filtrate was concentrated to give a light brown residue which was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a light brown oil (380 mg, 57.7%). 1H-NMR (CDCl3) δ: 7.09 (dd, J=2.4, 8.7 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 6.46 (d, J=8.7 Hz, 1H), 3.42 (t, J=7.8 Hz, 2H), 3.29 (t, J=5.7 Hz, 2H), 2.76-2.55 (m, 8H), 1.95-1.89 (m, 2H), 1.82-1.77 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:11][C:12]1[C:20]([O:21]C2CCCCO2)=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][N:16]2C1CCCCO1)[CH2:9][CH3:10].[OH-].[Na+]>ClCCl>[CH2:8]([O:11][C:12]1[C:20]([OH:21])=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2)[CH2:9][CH3:10]
Reactant: CCCOc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1c(O)ccc2[nH]ncc12
Reaction time: 2.5 h
Yield: 74384.8 %

Procedure:
Under a nitrogen atmosphere, trifluoroacetic acid (5.5 ml) was added to a solution of 4-propoxy-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (852.6 mg) in dichloromethane (16.5 ml) at room temperature. After 2.5 hours, the reaction solution was poured onto ice, adjusted to pH 7 with an aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The extract solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The residue purified was concentrated under reduced pressure and the resulting residue was washed with diethyl ether/hexane by repulping to obtain 4-propoxy-1H-indazol-5-ol (338.2 g, 80%, two steps).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][C:11]=2[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([N:31]([CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34]Cl)[CH3:30]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][C:11]=2[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:34][CH2:33][CH2:32][N:31]([CH2:36][CH3:37])[CH2:29][CH3:30])=[CH:18][CH:17]=1)(=[O:14])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc2oc(Cc3ccccc3)c(S(=O)(=O)c3ccc(O)cc3)c2c1
Reactant: CCN(CC)CCCCl
Product: CCc1ccc2oc(Cc3ccccc3)c(S(=O)(=O)c3ccc(OCCCN(CC)CC)cc3)c2c1

Procedure:
Reaction of 2-benzyl-5-ethyl-3-(4-hydroxyphenylsulfonyl)benzofuran with 3-diethylaminopropyl chloride as described above gives the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[Cl:57])[C:44]1=[O:58]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[Cl:57])[C:44]1=[O:58])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCCCN(Cc2ccccc2Cl)C1=O
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(Cc4ccccc4Cl)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(2-chlorobenzyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 48 (3.6 mg, 0.012 mmol) to give a white solid (7.0 mg, 69% yield). Anal. Calcd. for C44H53ClN4O6S m/z 800.4. found: 801.4 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.39-7.32 (m, 1H), 7.25-7.17 (m, 7H), 7.18-7.11 (m, 6H), 6.92 (t, J=7.70 Hz, 2H), 5.32 (t, J=4.67 Hz, 1H), 5.17-5.10 (m, 1H), 4.97 (t, J=6.87 Hz, 1H), 4.81 (d, J=15.40 Hz, 1H), 4.68-4.63 (m, 1H), 4.63-4.57 (m, 1H), 3.68 (s, 3H), 3.50 (dd, J=15.40, 11.55 Hz, 1H), 3.29-3.11 (m, 2H), 2.92-2.75 (m, 3H), 2.75-2.66 (m, 2H), 2.46-2.30 (m, 3H), 2.03-1.99 (m, 2H), 1.89-1.79 (m, 2H), 1.77-1.45 (m, 13H).
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[H-].[Na+].C(OC([C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:23][N:22]4[CH2:32][CH2:33][CH2:34][C:21]=34)[CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)=O)C>CN(C=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:31][C:27]1[N:26]=[C:25]([C:24]2[C:20]([C:17]3[CH:18]=[CH:19][C:14]4[N:15]([C:11]([C:1]([NH2:3])=[O:2])=[CH:12][N:13]=4)[CH:16]=3)=[C:21]3[CH2:34][CH2:33][CH2:32][N:22]3[N:23]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cnc2ccc(-c3c(-c4cccc(C)n4)nn4c3CCC4)cn12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(C(N)=O)n4c2)CCC3)n1
Temperature: 155 °C
Yield: 99 %

Procedure:
Add formamide (36 mL) to a suspension of sodium hydride (2.04 g, 60% dispersion in mineral oil, 51.1 mmol) and 6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (3.6 g, 9.29 mmol) in DMF (15 mL) over 10 min. Heat at 155° C. for 40 min, cool, dilute with ethyl acetate, and carefully dilute with saturated aqueous sodium bicarbonate. Filter any un-dissolved solid and wash with ethyl acetate. Concentrate the remaining organic layer and adsorb onto a 1:1 mixture of SiO2 and Celite®. Flash chromatography using ethyl acetate methanol mixtures followed by trituration of the combined lots in diethyl ether gives the titled compound (3.32 g, 99%) as a white solid. TOF MS ES+ exact mass calculated for C10H9IN2O2 (p+1): m/z=359.1620 Found: 359.1617.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH:8]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)[CH:9]1[CH2:14][CH2:13][O:12][C:10]1=[O:11].[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1.O>[C:22]([O:7][CH:8]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)[CH:9]1[CH2:14][CH2:13][O:12][C:10]1=[O:11])(=[O:24])[CH3:23]
Reactant: O=C1OCCC1C(O)C1CC2C=CC1C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC(C1CCOC1=O)C1CC2C=CC1C2
Reaction time: 10 h
Yield: 98 %

Procedure:
To 127 g of pyridine were added 208 g of α-[hydroxy(5-norbornen-2-yl)methyl]-γ-butyrolactone (Monomer 1), 123 g of acetic anhydride and 6 g of 4-dimethylaminopyridine. Reaction was effected at 25° C. for 10 hours. Water, 30 g, was added to the reaction mixture to stop reaction, followed by hexane extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. Purification by silica gel column chromatography yielded 245 g (yield 98%) of α-[acetoxy(5-norbornen-2-yl)methyl]-γ-butyrolactone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]3[N:26]=[C:25]([C:27]4[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=4)[CH:24]=[CH:23][C:10]=3[CH:11]([C:12]([CH3:22])([CH3:21])[C:13](=[O:20])[NH:14][C:15]3[S:16][CH:17]=[N:18][N:19]=3)[C:5]2=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH3:21][C:12]([CH:11]1[C:5]2[C:6](=[N:7][C:2]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:3][CH:4]=2)[O:8][C:9]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([N:33]([CH3:34])[CH3:35])=[O:32])=[CH:36][CH:37]=3)[CH:24]=[CH:23][C:10]1=2)([CH3:22])[C:13](=[O:20])[NH:14][C:15]1[S:16][CH:17]=[N:18][N:19]=1
Reactant: C1COCCN1
Reactant: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(Cl)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(N4CCOCC4)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1

Procedure:
Using conditions described for synthesis of Example 67, the ester from Step 3 of Example 54 was reacted with morpholine and converted Example 69. 1H NMR (400 MHz, chloroform-d) δ ppm 8.88 (1H, s), 8.10 (2H, d, J=8.31 Hz), 7.56-7.61 (1H, m), 7.48-7.56 (3H, m), 7.32 (1H, d, J=8.31 Hz), 6.38 (1H, d, J=8.31 Hz), 4.44 (1H, s), 3.82 (4H, t, J=4.78 Hz), 3.47-3.63 (4H, m), 3.19 (3H, s), 3.05 (3H, s), 1.25 (6H, s); MS (ES+) m/z: 586 (M+H); LC retention time: 3.62 min (analytical HPLC Method A).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:11]([C:16]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:19]3[C:20]([C:30]([NH:32][CH3:33])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:39][S-:40].[Na+]>CC#N.C(O)(C)C>[CH:36]1([C:35]2[C:16]([N:11]([C:4]3[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([S:40][CH3:39])[CH:3]=3)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=3[CH:34]=2)[CH2:38][CH2:37]1
Reactant: C[S-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(SC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (2 g, 3.58 mmol), and sodium thiomethoxide (0.685 g, 9.78 mmol) was dissolved in 20 mL of 1:1 CH3CN/Isopropanol and was stirred at room temperature for 3 h. Solvent was evaporated and water (60 mL) was added. The yellowish solid formed was filtered, washed with water to provide light yellowish solid which was used in the next step. (1.6 g, 86%) LCMS (m/z, ES+)=570 (M+H+).
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])=[CH:10][CH2:11]1)[C:7](=[O:14])[CH2:6][CH:5]2[CH3:15])([CH3:3])=[CH2:2]>CO.[Pd]>[CH:1]([C:4]12[CH2:13][CH:8]([CH:9]([CH3:12])[CH2:10][CH2:11]1)[C:7](=[O:14])[CH2:6][CH:5]2[CH3:15])([CH3:3])[CH3:2]
Reactant: C=C(C)C12CC=C(C)C(C1)C(=O)CC2C
Agent: [Pd]
Solvent: CO
Product: CC1CCC2(C(C)C)CC1C(=O)CC2C
Reaction time: 5 h
Yield: 21.6 %

Procedure:
At 25° C., a mixture of 1 g 5-isopropenyl-4,8-dimethylbicyclo[3.3.1]non-7-en-2-one (4.9 mmol) and 50 mg 10% Pd/C in 10 ml MeOH was stirred under 10 bar of H2 for 5 h. Filtration (Celite®), concentration, and FC (SiO2, hexane/Et2O 100:7) gave 0.22 g (22%) of compound 9. The boiling point of the end product is 75° C. at 0.07 torr (0.09 mbar).