Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:9][C:3]1([C:1]#[C:2][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2/[C:13](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:14](=[O:20])[NH:15]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C#CC1(O)CCCCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC3(O)CCCCC3)c21

Procedure:
Using Method C above, 1-ethynyl-1-cyclohexanol (60 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield (Z)-1,3-dihydro-4-[(1-hydroxycyclohexyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 94 mg, 65%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].C1(C)C=CC=CC=1>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1OC(C)C
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1OC(C)C
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A mixture of methyl 4-iodo-2-isopropoxybenzoate (4.10 g), (2,4-difluorophenyl)boronic acid (4.04 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.789 g), a 2 M aqueous sodium carbonate solution (19.2 mL), tris(dibenzylideneacetone)dipalladium(0) (0.821 g), and toluene (50 mL) was stirred at 100° C. for 2 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature. Then, the organic layer was separated and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.90 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]2Cl.[OH:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[CH:21]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]2[NH:24][C:23]1[CH:25]=[CH:26][C:20]([OH:19])=[CH:21][C:22]=1[CH3:27]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: CCO
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(O)cc1C

Procedure:
Ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (2.6 g, 0.0098 mol) and 4-hydroxy-2-methylaniline (2.4 g, 0.0196 mol) in ethanol (150 ml) were heated under refulx for 30 minutes. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform and extracted with 2N hydrochloric acid (3×100 ml). On basification of the chloroform extracts, a solid precipitated out, this was collected by filtration and dried. Recrystallisation from dimethylformamide gave the title compound. Yield=2.52 g, m.p. 277°-279° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1.O.[NH2:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][C:25]([OH:27])=[O:26]>>[CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1.[NH2:22][C@H:23]([C:28]([O-:30])=[O:29])[CH2:24][C:25]([O-:27])=[O:26].[CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[C:14]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[CH2:4][CH2:3]1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: CN1CCc2cccc3c2[C@H]1Cc1ccc(O)c(O)c1-3
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]

Procedure:
Apomorphine aspartate solution was prepared by dissolving apomorphine base in 0.1M aspartic acid solution. Water was added to obtain a molar ratio of 1:1, apomorphine:aspartic acid, at a final concentration of 2% apomorphine. The pH of the solution was 4.9.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(N(CC)CC)C.B.[Na]>CO>[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1cccc(C=O)c1OC
Reactant: COc1ccc(C(O)CN)cc1OC
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(O)CNCc2cccc(OC)c2OC)cc1OC
Temperature: 25 °C

Procedure:
1.0 g of α-(aminomethyl-3,4-dimethoxybenzyl alcohol hydrochloride was suspended in 5 ml of methanol, and after adding thereto 0.85 g of 2,3-dimethoxybenzaldehyde, 0.63 ml of triethylamine was added dropwise to the mixture while stirring at room temperature. The mixture was heated under reflux for 30 minutes, and 0.24 g of sodium boron hydride was added slowly to the mixture while stirring under ice cooling. After the foaming stopped, the mixture was concentrated. The residue was subjected to a separating procedure with chloroform and water, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 1.07 g of α-[[(2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol, m.p. 96°-97° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]3[C:24](=[O:35])[N:25]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[CH:29]=[O:30])[N:26]=[C:7]3[C:6]=2[C:5]([F:36])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:17][CH:18]=3)[CH:9]=[C:8]3[C:24](=[O:35])[N:25]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[CH2:29][OH:30])[N:26]=[C:7]3[C:6]=2[C:5]([F:36])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1-n1nc2c3c(F)ccc(F)c3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3c(F)ccc(F)c3c-2nn1-c1ccccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(6,9-Difluoro-3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzaldehyde [(Example 39) 15 mg, 0.31 mmol] was dissolved in methanol (3 mL), treated with sodium borohydride (4 mg, 0.62 mmol, 2 equiv) and stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 80:20; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.46 (1H, s), 7.91 (1H, d, J=2.5 Hz), 7.75-7.70 (3H, m), 7.56 (1H, dd, J=7.3, 1.3 Hz), 7.45 (1H, td, J=7.6, 1.5 Hz), 7.38 (1H, td, J=7.4, 1.4 Hz), 7.30-7.17 (5H, m), 6.48 (1H, dd, J=2.4, 1.7 Hz), 5.66 (1H, d, J=2.4 Hz), 4.52 (2H, br s) ppm; high resolution mass spectrometry (ES+) m/z 484.1567 [(M+H)+; calculated for C27H20F2N5O2: 484.1580].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[C:17]1([S:23]([C:26]2[C:27]([Cl:33])=[N:28][S:29][C:30]=2[CH:31]=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:30]2[S:29][N:28]=[C:27]([Cl:33])[C:26]=2[S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:24])=[O:25])=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1snc(Cl)c1S(=O)(=O)c1ccccc1
Product: COC(=O)Cn1c(C)c(Cc2snc(Cl)c2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 4-benzenesulfonyl-3-chloroisothiazole-5-carbaldehyde.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH2:29]([NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1ccccc1
Product: CC(C(=O)NCc1ccccc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=455.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-benzyl-malonamic acid.
Reaction SMILES: II.[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][SH:8].[OH-].[Na+]>CCOCC>[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][S:8][S:8][CH2:7][CH2:6][CH2:5][N:4]([CH3:9])[CH3:3]
Reactant: CN(C)CCCS
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CN(C)CCCSSCCCN(C)C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
Iodine is added portionwise to a mixture of 4 g of 3-dimethylaminopropylmercaptan in 60 ml of ether and 30 ml of 2-N sodium hydroxide solution until the solution is no longer decolorised each time (ca 4.2 g of iodine). After stirring for 1 hour, the ether phase is dried over magnesium sulphate, concentrated and fractionally distilled at 95°-100° C./0.025 mmHg. 2.7 g (68%) of 3-dimethylaminopropyl disulphide are obtained in the form of a clear colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:36](=[O:35])[CH2:37][OH:38])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Product: C[C@H](NC(=O)CO)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 5 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and 2-chloro-2-oxoethyl acetate (21 mg, 150 μmol). Yield 18 mg (76%).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[CH:2].[NH2:11][C:12]1([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[C:22]([CH3:33])[CH:21]=2)=[O:18])[CH2:16][CH2:15][O:14][CH2:13]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([C:3]1[S:7][C:6]([C:8]([NH:11][C:12]2([C:17](=[O:18])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C:27]4=[O:32])=[C:22]([CH3:33])[CH:21]=3)[CH2:16][CH2:15][O:14][CH2:13]2)=[O:10])=[CH:5][CH:4]=1)#[CH:2]
Reactant: Cc1cc(NC(=O)C2(N)CCOC2)ccc1N1CCOCC1=O
Reactant: C#Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C#Cc1ccc(C(=O)NC2(C(=O)Nc3ccc(N4CCOCC4=O)c(C)c3)CCOC2)s1

Procedure:
Prepared analogously to Example 1a from 5-ethynylthiophene-2-carboxylic acid and 3-amino-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]tetrahydro-furan-3-carboxamide with TBTU and NMM in DMF.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[C:23]([O-:26])(=[O:25])[CH3:24].[K+]>CN(C=O)C.O>[C:23]([O:26][CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 1.32 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole in 30 ml of dry DMF was added 1.58 g of potassium acetate. After stirring at room temperature overnight, the reaction mixture was diluted with water and extracted with benzene. The organic phase was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene to yield 0.96 g of 3-acetoxymethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, nD23 1.5635.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([C:20]#[CH:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[C:21]#[C:20][C:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[C:16]([Cl:22])[CH:17]=1)[CH3:28]
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of diisopropylamine (0.23 mL) in THF (0.6 mL) at −78° C. was added a solution of n-butyllithium (0.46 mL, 2.0 M in hexane). The mixture was stirred at −78° C. for 20 minutes, 0° C for 15 min., and cooled to −78° C. To this mixture was added a solution of 1,3-dichloro-5-ethynyl-benzene (136 mg, 0.80 mmol) in THF (1.0 mL) over 2 minutes. After stirring at −78° C. for 1 h, a solution of ethyl chloroformate (0.09 mL) in THF (0.2 mL) was added, and stirred for 1 h at −78° C. The reaction was quenched with saturated ammonium chloride, warmed up to ambient temperature, and extracted with ethyl acetate. The extract was dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with hexane to give the title compound (0.16 g, 87% yield) as a yellow oil. 1H NMR (CDCl3) δ 7.47-7.44 (m, 3H), 4.31 (q, 2H, J=7.2 Hz), 1.36 (t, 3H, J=7.2 Hz).
Reaction SMILES: C([O:5][C:6](=[O:57])[CH2:7][CH2:8][C@H:9]([NH:23][C:24]([C:26]1[N:30]2[C@:31]([CH3:56])([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:47][CH:46]=3)[C:32](=[O:43])[N:33]([C:34]3[CH:39]=[C:38]([Cl:40])[C:37]([F:41])=[C:36]([Cl:42])[CH:35]=3)[C:29]2=[N:28][CH:27]=1)=[O:25])[C:10](=[O:22])[NH:11][C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:13][CH3:14])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:40][C:38]1[CH:39]=[C:34]([N:33]2[C:29]3=[N:28][CH:27]=[C:26]([C:24]([NH:23][C@H:9]([C:10](=[O:22])[NH:11][C:12]([CH3:21])([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:13][CH3:14])[CH2:8][CH2:7][C:6]([OH:57])=[O:5])=[O:25])[N:30]3[C@:31]([CH3:56])([CH2:44][C:45]3[CH:46]=[CH:47][C:48]([O:51][C:52]([F:54])([F:53])[F:55])=[CH:49][CH:50]=3)[C:32]2=[O:43])[CH:35]=[C:36]([Cl:42])[C:37]=1[F:41]
Reactant: CCC(C)(NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cnc2n1[C@](C)(Cc1ccc(OC(F)(F)F)cc1)C(=O)N2c1cc(Cl)c(F)c(Cl)c1)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC(C)(NC(=O)[C@H](CCC(=O)O)NC(=O)c1cnc2n1[C@](C)(Cc1ccc(OC(F)(F)F)cc1)C(=O)N2c1cc(Cl)c(F)c(Cl)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.7 %

Procedure:
To a solution of (S)-4-{[(R)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-4-(1-methyl-1-pyridin-2-yl-propylcarbamoyl)-butyric acid tert-butyl ester (116 mg, 0.142 mmol) in 2 mL of CH2Cl2 was added HCl in dioxane (0.177 mL, 0.708 mmol). The reaction mixture was stirred at room temperature for 6 h. An additional portion of HCl in dioxane (0.177 mL, 0.708 mmol) was added, and the reaction mixture was stirred for 4 h and then concentrated to a colorless oil. The residue was purified by reverse-phase HPLC (20-90% CH3CN/H2O, 0.1% TFA) to give 45 mg (42%) of the title compound, isolated as the TFA salt, m/z 763.8 [M+1]+.
Reaction SMILES: Cl[CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>O>[OH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:2][P:3]([OH:6])(=[O:5])[OH:4]
Reactant: NCCCCCCCCCCCCN
Reactant: O=P(O)(O)CCl
Solvent: O
Product: NCCCCCCCCCCCCNCP(=O)(O)O

Procedure:
Chloromethanephosphonic acid (15.1 g, 115.7 mmoles) and 1,12-diaminododecane (100 g, 0.5 moles) were heated under reflux in water (160 cm3) for 20 hours. The water was then distilled off and ethanol (250 cm3) was added. The phosphonic acid was filtered off and dried. The crude yield was 30.7 g (85%). A sample was purified by recrystallization from water/ethanol to give N-(12-aminododecyl)-aminomethanephosphonic acid monohydrate as a fine white crystalline solid having a melting point of 234° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][C@H:17]([C:19]([F:22])([F:21])[F:20])[CH2:16][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][O:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].CCO>[Fe].O>[NH2:1][C:4]1[C:5]([N:13]2[CH2:18][C@H:17]([C:19]([F:22])([F:20])[F:21])[CH2:16][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][O:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c(N)cnc3c2CCO3)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a mixture of tert-butyl [(3S,5R)-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (227.1 mg, 0.5252 mmol), iron powder (289.6 mg, 5.186 mmol) and ammonium chloride (462.4 mg, 8.644 mmol) was added EtOH (5.0 mL) followed by water (2.5 mL). The mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was eluted with a 10% aqueous solution of K3PO4 (50 mL), and EtOAc (50 mL). The separated organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude sub-title compound (211.5 mg). The crude product was used directly in the next step without further purification. LCMS calc. for C18H26F3N4O3 (M+H)+: m/z=403.2. found 403.2.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:11])=[CH:7][CH:8]=2)/[C:3]/1=[CH:12]/[C:13]([NH2:15])=[O:14].[C:16]([O-:19])(=[O:18])[CH3:17].[K+].C1OCCOCCOCCOCCOCCOC1.C(O)(=O)C>C(#N)C.C(O)C>[C:16]([O:19][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:11])=[CH:7][CH:8]=2)/[C:3]/1=[CH:12]/[C:13]([NH2:15])=[O:14])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: NC(=O)/C=C1/c2cc(F)ccc2CC1Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)OC1Cc2ccc(F)cc2/C1=C/C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
A mixture of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide (0.51 g, 1.90 mmoles), potassium acetate (0.37 g, 3.80 mmoles), and 18-crown-6 (0.06 g, 0.24 mmoles, Aldrich) in acetonitrile (20 mL) and ethanol (10 mL) was sonicated using a Sonicor ultrasonicator for 2 hours, allowing the temperature to rise to 35° C. The mixture was stirred overnight at ambient temperature. Glacial acetic acid (3 mL) was added and the mixture was sonicated for 1.5 hours allowing the temperature to rise to 50° C. The mixture was stirred overnight at ambient temperature and evaporated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with water (2×50 mL) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane:ethyl acetate (3:1) gradually increasing the polarity to 100% ethyl acetate. The fractions containing the compound with Rf=0.3 in hexane:ethyl acetate (1:1) were combined and evaporated in vacuo to give a solid which was washed with hexane and dried in a vacuum at 50° C. for 18 hours to give 0.22 g (46%) of (Z)-2-(2-acetoxy-6-fluoro-1-indanylidene)acetamide as a white solid, mp 202°-203° C.; 1H-NMR (DMSO-d6): d 7.49 and 7.08 (d, 2H), 7.19-7.38 (m, 3H), 6.57 (s, 1H), 6.42 (d, 1H), 3.39 (dd, 1H, J=6.9 Hz, 17.7 Hz), and 2.82 (d, 1H, J=18.0 Hz), 1.91 (s, 3H); steady-state nOe: irradiation at 6.57 d, observed 22% nOe at 7.35 d.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[Br:14][CH2:15][CH2:16][CH2:17]Br.[H-].[Na+]>CN(C=O)C>[Br:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1O)CCC2=O
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCCBr)CCC2=O

Procedure:
A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H) (5.0 g, 0.028 mole), 1,3-dibromopropane (5.7 mL, 0.056 mole) and sodium hydride (1.2 g, 0.028 mole) were stirred in 50 mL of DMF at room temperature overnight under Argon. The reaction mixture was quenched with water (150 mL), extracted with ethyl acetate, then washed with 1N HCl and brine. The extract was dried over sodium sulfate and the solvent removed in vacuo to yield the title compound, 5-(3-Bromo-propoxy)-6-methoxy-indan-1-one. MS m/z 297 (M+H)+.