Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:46](=[O:47])[CH2:45][N:42]3[C:43]([CH3:44])=[C:39]([Cl:38])[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41]3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Br)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Bromophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.36 (d, 2H), 6.92 (d, 2H), 5.37 (s, 2H), 3.60 (m, 4H), 3.24 (m, 2H), 3.14 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expect=465.0, found=465.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH2:26][OH:27].C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([CH:26]=[O:27])=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CO)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of (2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)methanol (5.03 g) and triethylamine (5.7 mL) in DMSO (80 mL) was added sulfur trioxide pyridine complex (4.35 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.37 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].OS(O)(=O)=O>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: CCOCC
Product: OCCC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
57.9 g (0.221 mol) of 3,3-bis(4-fluorophenyl)propionic acid were dissolved in 200 ml of absolute ether and the solution was added dropwise to a suspension of 10.9 g (0.287 mol) of LiAlH4 in 150 ml of absolute ether. When the dropwise addition had ended, the mixture was subsequently stirred for a further 30 minutes and, for hydrolysis, 175 ml of saturated sodium potassium tartrate solution and 400 ml of 10% strength H2SO4 were added dropwise in succession. After filtration, the phases were separated and the ethereal phase was washed with NaHCO3 solution and NaCl solution, dried and concentrated.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]#[N:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=2)[C:7]([C:22]#[N:23])=[C:6]([SH:24])[N:5]=1)[CH3:2].Cl[CH2:26][C:27]1[N:28]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[O:30][CH:31]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[O:30][CH:31]=[C:27]([CH2:26][S:24][C:6]3[C:7]([C:22]#[N:23])=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=4)[C:9]([C:10]#[N:11])=[C:4]([O:3][CH2:1][CH3:2])[N:5]=3)[N:28]=2)=[CH:37][CH:36]=1
Reactant: CCOc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
100 mg (0.293 mmol) of 2-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitrile together with 73 mg (0.322 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 98 mg (1.172 mmol) of sodium bicarbonate are stirred in 2 ml of DMF at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5). This gives 41.5 mg (26% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][C:5]2[O:6][C:7]([C:14]([O:16]CC)=[O:15])=[C:8]([C:9]([O:11]CC)=[O:10])[C:4]=2[CH:3]=1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][C:5]2[O:6][C:7]([C:14]([OH:16])=[O:15])=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1oc2cc(OC)c(Br)cc2c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2oc(C(=O)O)c(C(=O)O)c2cc1Br
Yield: 84.9 %

Procedure:
Diethyl 5-bromo-6-methoxybenzo[b]furan-2,3-dicarboxylate (D11) (1.26 g, 3.4 mmoles) in ethanol (20 ml) and water (5 ml) was treated with 20% sodium hydroxide solution (5 ml) and heated under reflux for 3 hrs. The mixture was cooled and the ethanol removed in vacuo. The mixture was acidified to pH1 with hydrochloric acid. Filtration of the solid and drying gave the title compound (D12) (0.91 g, 85%)
Reaction SMILES: O.[ClH:2].Cl.Cl.Cl.[NH2:6][CH:7]([CH:38]([CH3:40])[CH3:39])[CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[C:31]([O:32]C)=[CH:30][C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[N:23]=3)[C:19]3[CH:34]=[CH:35][CH:36]=[CH:37][C:18]=3[N:17]=2)[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].BrB(Br)Br.[NH4+].[OH-]>ClCCl>[OH2:32].[ClH:2].[ClH:2].[ClH:2].[ClH:2].[NH2:6][CH:7]([CH:38]([CH3:40])[CH3:39])[CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[C:31]([OH:32])=[CH:30][C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[N:23]=3)[C:19]3[CH:34]=[CH:35][CH:36]=[CH:37][C:18]=3[N:17]=2)[CH2:11][CH2:10]1
Reactant: COc1cc2c(nc1Cn1c(NC3CCN(CC(N)C(C)C)CC3)nc3ccccc31)CCCC2
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)C(N)CN1CCC(Nc2nc3ccccc3n2Cc2nc3c(cc2O)CCCC3)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(5,6,7,8-tetrahydro-3-methoxy-2-quinolinyl)methyl]-1H-benzimidazol-2-amine tetrahydrochloride monohydrate (0.0021—O— mol) was basified with K2CO3 10%. The mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, to give A′. A mixture of A′ in dichloromethane (50 ml) was cooled to 0° C. A solution of tribromoborane in dichloromethane (0.01526 mol) was added dropwise. The mixture was stirred at room temperature overnight, poured out on ice, basified with a concentrated NH4OH solution, decanted and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 90/10/0.5; 20–45 μm). The desired fractions were collected and the solvent was evaporated. The residue was converted into the hydrochloric acid salt salt (1:4) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 0.5 g (37%) of (±)-N-[1-(2-amino-3-methylbutyl)4-piperidinyl]-1-[(5,6,7,8-tetrahydro-3-hydroxy-2-quinolinyl)methyl]-1H-benzimidazol-2-amine tetrahydro-chloride monohydrate; mp. 240° C. (comp. 63).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-3-(2,5-difluorophenyl)-propionic acid (8.0 g, 27 mmol) in anhydrous dichloromethane (200 mL) at 0° C. is added N-ethyl-N′,N′-dimethylaminoethyl carbodiimide (5.09 g, 27 mmol), followed by 4-nitrophenol (4.4 g, 32 mmol). After stirring for 30 min, the solution is washed sequentially with saturated NaHCO3 (aq), water, 1.0 M citric acid (aq), water and brine, then dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a slightly red solid (8.11 g, 19 mmol), contaminated with residual 4-nitrophenol, which may be used without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1F)[N:11]=[CH:10][C:9]([C:16]#[N:17])=[C:8]2[NH:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1>COCCO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:27][CH2:22][CH2:23][O:25][CH3:26])[N:11]=[CH:10][C:9]([C:16]#[N:17])=[C:8]2[NH:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1
Reactant: COc1cc2c(Nc3cc(OC)c(OC)c(OC)c3)c(C#N)cnc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: COCCO
Product: COCCOc1cc2ncc(C#N)c(Nc3cc(OC)c(OC)c(OC)c3)c2cc1OC
Temperature: 25 °C
Yield: 152.8 %

Procedure:
A mixture of sodium hydride (80 mg, 2.0 mmol) and 6-methoxy-7-fluoro-4-[(3,4,5-tri-methoxyphenyl)amino]-3-quinolinecarbonitrile (203 mg, 0.53 mmol) in 2-methoxyethanol (6 mL) is heated at reflux for 2 hours. Additional sodium hydride (80 mg, 2.0 mmol) is added and the reaction mixture is heated at reflux for 4 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ethyl acetate and diethyl ether provides 178 mg of 6-methoxy-7-[2-methoxyethoxy]-4-[(3,4,5-trimethoxyphenyl)amino]-3-quinolinecarbonitrile, mp 188-190° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:25])[N:6]2[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1nc(Sc2ccccc2)nc2c1ncn2Cc1ccccc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(Sc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 22 %

Procedure:
6-Amino-9-benzyl-2-phenylthiopurine (95 mg, 0.28 mmol) and bromine (0.4 ml) were dissolved in 150 ml of methylene chloride and the solution was stirred at room temperature for 4.5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtered was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (25 mg, yield 22%).
Reaction SMILES: [NH2:1][CH:2]([CH3:28])[C:3]([NH:5][C:6]1[N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:8]=[C:9]([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:10]=1)=[O:4].[F:29][C:30]1[CH:31]=[C:32]([CH:38]=[C:39]([F:41])[CH:40]=1)[C@H:33]([OH:37])[C:34](O)=[O:35].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C1COCC1>[C:24]([N:7]1[C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:1][C:34](=[O:35])[CH:33]([C:32]2[CH:38]=[C:39]([F:41])[CH:40]=[C:30]([F:29])[CH:31]=2)[OH:37])[CH3:28])=[CH:10][C:9]([C:11]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[N:8]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CC(N)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Reaction time: 16 h

Procedure:
A solution of 0.14 g (0.4 mmol) of 2-amino-N-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]propionamide and 0.08 g (0.4 mmol) of (S)-3,5-difluoromandelic acid (Garofalo, et al. Bioorg. Med. Chem. Lett. 2002, 12, 3051) in 5.0 mL of THF was stirred at rt as 0.06 g (0.4 mmol) of HOBT and 0.08 mL (0.7 mmol) of NMM was added followed by 0.90 g (0.5 mmol) of EDC.HCl. After 16 h, the reaction was quenched with 1M HCl and extracted with EtOAc. The organic layer washed with sat. aq. NaHCO3, dried over MgSO4 and concentrated. Purification on silica gel using 4% Et3N-MeOH as eluant afforded N-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]-2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]propionamide.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1.[CH2:26]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29]>CN(C)C=O>[CH2:26]([N:30]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1)[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCNCCCC
Reactant: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2ccccc2-3)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
A solution of 711 mg (2.0 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 10 ml of N,N-dimethylformamide was treated with 1.0 ml (6.0 mmol) of dibutylamine and stirred at room temperature under argon for 3 hrs. The solution was evaporated, the residue was triturated in 10 ml of water and the crystals were filtered off under suction. The crude product was dissolved in methylene chloride, the solution was dried with sodium sulfate, whereupon it was chromatographed on 30 g of silica gel (methylene chloride/acetone 9:1, then 4:1). There was obtained 0.73 g of (S)-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, which was converted in 10 ml of acetonitrile with ethereal hydrochloric acid into the hydrochloride. By crystallization from hot ethyl acetate there was obtained 0.75 g (77%) of (S)-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one hydrochloride (1:1) of m.p. 115°-123° (dec.).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]2=[CH:17][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([Cl:25])[C:23]=3[O:24][CH:14]2[C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:25][C:22]1[C:23]2[O:24][C:14]3[C:13](=[O:26])[N:12]([C@@H:4]([CH2:5][CH:6]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[C:3]([OH:27])=[O:2])[CH2:16][C:15]=3[CH2:17][C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC2=Cc3cccc(Cl)c3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 79.8 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid methyl ester (1.5 g, 4.0 mmol) and lithium hydroxide monohydrate (0.22 g, 5.22 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (50 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N-hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (1.2 g, 83.3%) as off white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3cc(C(F)(F)F)ccn3)CC2)cc1
Yield: 39.1 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2-chloro-4-(trifluoromethyl)pyridine (94 μl, 0.72 mmol), DIEA (0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185° C. to afford the title compound (60 mg), an off-white solid, in 39% yield.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1.Cl>CO.[Fe]>[CH3:1][S:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11]
Reactant: CSCCc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CSCCc1cccc(N)c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of methyl(3-nitrophenethyl)sulfane (4.4 g, 22 mmol) and iron powder (3.75 g, 67 mmol) in MeOH was stirred at room temperature, then aqueous HCl (20 g, 36.5%) was added slowly, then the mixture solution was heated to reflux for 3 hours. The solvent was evaporated, and saturated sodium bicarbonate was added, the aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give 3-(2-(methylthio)ethyl)aniline (3.5 g, yield 94%). 1H NMR: 400 MHz CDCl3 δ 7.11-7.07 (m, 1H), 6.63-6.61 (m, 1H), 6.56-6.54 (m, 1H), 3.64 (s, 2H), 2.83-2.71 (m, 4H), 2.13 (s, 3H).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](O)[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].C(Cl)[Cl:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCCC.C(Cl)(Cl)(Cl)Cl>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([Cl:20])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
Via chloride: A solution of 374 g (1.48 mol) (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 1.61 CH2Cl2 was treated with 680 g (2.6 mol) triphenylphosphine, cooled to 3-5° C. and treated in 10 min with 1.241 (12.8 mol) CCl4, after 2 h at this temperature cooling was stopped, the reaction temperature was raised during 2 h to 35° C. It was cooled down to 20° C. and stirred for further 45 min. After addition of 4 l of n-heptane, the reaction was evaporated to 2.9 l, cooled to 0° C., filtered, the residue was treated twice the same way, the third time by dissolving the residue again in 2 l of CH2Cl2. The solvents were evaporated and filtered through silica gel with hexane/tert.-butyl-methylether 9:1 as eluent. Evaporation of the solvents gave 347 g (89%) of (2S,4S)-4-chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 246 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.Cl.Cl.[C:17]12([CH2:24][N:25]3[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26]3)[O:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.CCN(CC)CC.O>CC(N(C)C)=O>[C:17]12([CH2:24][N:25]3[CH2:29][CH2:28][C@@H:27]([NH:30][C:2]4[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=4)[CH2:26]3)[O:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18]2
Reactant: N[C@@H]1CCN(CC23CCC(CC2)O3)C1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(CC34CCC(CC3)O4)C2)cn1
Temperature: 100 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To a mixture of ethyl (2E)-3-(5-chloropyrazin-2-yl)acrylate (242.8 mg) in DMA (1.9 mL) was added (3R)-1-(7-oxabicyclo[2.2.1]hept-1-ylmethyl)pyrrolidin-3-amine dihydrochloride (370 mg) and Et3N (796 uL), which was stirred at 100° C. for 24 hours. To the resultant was added H2O, which was extracted with AcOEt. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-(7-oxabicyclo[2.2.1]hept-1-ylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (425 mg) as a brown solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C(N(C(C)C)CC)(C)C.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)#[CH:33]>[Cu]I>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:32]2[N:3]=[N:2][N:1]([C:4]3[CH:9]=[CH:8][C:7]([C@@H:10]4[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]4)=[CH:6][CH:5]=3)[CH:33]=2)=[CH:35][CH:36]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N=[N+]=[N-])cc2)C1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-n3cc(-c4ccc(F)cc4)nn3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
(S)-tert-Butyl 2-(4-azidophenyl)morpholine-4-carboxylate (76 mg, 0.25 mol) was dissolved in diisopropylethylamine (800 mg, 6.24 mmol). 1-Ethinyl-4-fluorobenzene (30 mg, 0.25 mmol) was added, followed by copper(I)-iodide (48 mg, 0.25 mmol). The mixture was stirred for 2 h at room temperature. The green mixture was concentrated on the rotavap, silica gel (0.5 g) was added and after short grinding the mixture was put on a silica gel column for purification. Flash chromatography (5 g silica gel, 10 to 30% ethyl acetate in heptane) yielded a white solid (17 mg, 16%), MS (ISP): 425.2 ([M+H]+).