Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][CH:18]([C:29]([OH:31])=[O:30])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>>[C:29]([CH:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)([OH:31])=[O:30]
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1NC(Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with DL-tryptophan to provide the title compound in good yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>>[N:18]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1CCCCCN1CCCC1

Procedure:
As shown in the above Reaction Scheme 1, 1,5-dibromopentane is reacted with potassium phthalimide in a suitable solvent to give N-(5-bromopentyl)phthalimide (2). The compound (2) is reacted with pyrrolidine in the presence of potassium carbonate and sodium iodide to give N-(5-pyrrolidin-1-ylpentyl)phthalimide (3). The compound (3) is reacted with hydrazine to provide 5-(pyrrolidin-1-yl)pentylamine (4). The compound (4) is reacted with di-t-butyl dicarbonate to give t-butyl (5-pyrrolidin-1-ylpentyl) carbamate (5). Then, the compound (5) is reacted with lithium aluminum hydride in a suitable solvent to give N-methyl-N-[5-(pyrrolidin-1-yl)pentyl]amine (6).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-:25].[Na+]>COCCO>[C:23]([C:20]1[S:21][CH:22]=[C:18]([NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:19]=1)(=[O:25])[NH2:24]
Reactant: CCCCCCCCCCCCCCCCNc1csc(C#N)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: COCCO
Product: CCCCCCCCCCCCCCCCNc1csc(C(N)=O)c1
Reaction time: 8 h

Procedure:
A mixture of 6.9 g. of 4-hexadecylamino-2-cyanothiophene, 80 ml. of methyl cellosolve, and 80 ml. of 1 N sodium hydroxide is refluxed for 21 hours. After cooling in an ice bath, the solid is filtered and thoroughly washed with methylene chloride. The solid is then added to 100 ml. of water and 5 ml. of concentrated hydrochloric acid and stirred for 8 hours. The solid is filtered and recrystallized from isopropanol.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=O)[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[C@H:49]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:37][C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]([CH2:26][C@@H:25]([O:24][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]3[CH2:14][CH2:13][C:12]4[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=4[NH:10][C:9]3=[O:8])[CH2:17][CH2:18]2)=[O:23])[C:39]([N:56]2[CH2:57][CH2:58][CH:53]([N:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][C@H:49]3[C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:54][CH2:55]2)=[O:41])=[CH:28][C:29]=1[Cl:38]
Reactant: CCOC(=O)[C@@H]1CN(C)CCN1C1CCNCC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(C)CCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.40 mL (2.88 mmol) triethylamine were added to a mixture of 260 mg (0.46 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 210 mg (0.58 mmol) ethyl(S)-4-methyl-1-piperidin-4-yl-piperazine-2-carboxylate (Example A9f) and 170 mg (0.53 mmol) TBTU in 2.4 mL DMF and the reaction mixture was stirred for 18 h at RT. The reaction mixture was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.C([O-])([O-])=O.[K+].[K+].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(Sc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2,6-dinitrobenzonitrile (2.0 g, 10.36 mmol) and K2CO3 (1.43 g, 10.36 mmol) in 5 mL of anhydrous DMF was added PhSH (1.14 ml in 5 mL of DMF) dropwise under nitrogen at 0° C. After the completion of addition, the reaction mixture was stirred at 0° C. for 0.5 hr. Then the reaction mixture was poured into 50 mL of water, the resultant precipitation was collected by filtration, washed with water and dried in the air to give the title product.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:26][CH2:25][C:5]2([CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[C@H:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:6]2)[CH2:4][CH2:3]1>C(O)C.[OH-].[OH-].[Pd+2]>[F:27][C:2]1([F:1])[CH2:26][CH2:25][C:5]2([CH2:9][NH:8][C@H:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:6]2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)[C@@H]1CC2(CCC(F)(F)CC2)CN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CCC(F)(F)CC2)CN1
Yield: 93.1 %

Procedure:
To a solution of 3-ethyl 2-(phenylmethyl) (3S)-8,8-difluoro-2-azaspiro[4.5]decane-2,3-dicarboxylate (114) (630 mg, 1.65 mmol) in absolute ethanol (12 mL), was added 20% Pd(OH)2 on carbon (65 mg) and the reaction hydrogenated on a Fisher-Porter apparatus for 18 h at 60 psi. The reaction was filtered through celite and concentrated in vacuo to afford the title compound as a clear oil (380 mg, 93% yield).
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.CO.C(Cl)(Cl)Cl.CO.O.[CH2:33]([NH2:35])C>C(O)C.CO>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:14])[N:3]([C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17])[C:2]([NH:35][CH3:33])=[C:10]2[CH:11]=[O:12]
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: CCN
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: CNc1c(C=O)c2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 125 mg, 0.33 mmol) was dissolved in 33% ethylamine solution in ethanol (10 mL), and the resulting solution was stirred at room temperature for 30 min. The solvent was then evaporated to approx 1 mL, and diluted with EtOAc (50 mL). The suspension was washed with H2O (20 mL) and brine (50 mL), then dried over MgSO4, filtered and evaporated to yield a yellow residue. The residue was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 20% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a clear viscous residue which was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from MeOH/H2O to yield 56 mg (43%) of 4.18 as a white microcrystalline solid: mp 241-242 C; Rf 0.5 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 9.98 (s, 1H), 8.24 (s, 1H), 7.97 (q, 1H, D2O exch.), 7.69 (s, 1H), 5.93 (t, 1H, D2O exch.), 5.91 (d, 1H), 5.34 (d, 1H, D2O exch.), 5.32 (d, 1H, D2O exch.), 4.34 (q, 1H), 4.09 (t, 1H), 4.05 (s, 1H), 3.76-3.67 (m, 2H), 3.12 (d, 3H). 13C-NMR (125 MHz, DMSO-d6): δ 181.72, 154.48, 133.66, 127.05, 123.71, 122.72, 119.70, 110.91, 100.20, 88.56, 86.10, 70.78, 70.30, 60.80, 33.45. HRMS (ES) m/z calcd. for C15H16Cl2N2O5+H 375.0514. found 375.0511. Anal calcd for C15H16Cl2N2O5¼H2O: C, 47.45; H, 4.38; N, 7.38. Found: C, 47.53; H, 4.59; N, 7.26.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:11]2>C(Cl)Cl>[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:11]2
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2c(O)cccc2[nH]1
Temperature: -78 °C
Yield: 64 %

Procedure:
Boron tribromide (73.1 ml, 1.0 M solution in DCM) was added dropwise to a solution of methyl 4-methoxyindole-2-carboxylate (5 g) in DCM (200 ml) cooled to −78° C. under argon. The reaction was allowed to warm to room temperature then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-50% ethyl acetate as eluent to give the end product as a yellow solid (2.98 g, 64%); NMR δ (CD3SOCD3) 3.82 (s, 3H), 6.36 (d, 1H), 6.85 (d, 1H), 7.02 (t, 1H), 7.17 (d, 1H), 9.66 (s, 1H), 11.72 (bs, 1H); M/z (+) 192 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=[N+]([O-])CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To the mixture of 1-chloro-4-(4-(2-nitroethyl)phenoxy)-2-(trifluoromethyl)benzene (17 g, 49.2 mmol) and nickel(II) chloride hexahydrate (46.6 g, 197 mmol) in methanol (300 mL) at 0° C. was added NaBH4 (3.72 g, 98 mmol) portion wise. The reaction mixture was stirred at rt overnight. Purification via a column chromatography afforded the title compound as a yellow oil (8.86 g, 51.4% yield). LCMS: rt=2.51 min, [M+H+]=316.1
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]([O:14]CC)=O)=[N:10][CH:9]=[C:8]2[N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=[CH:19][C:7]=12)[CH3:2].[NH2:28][OH:29].[OH-].[Na+].Cl>CO>[CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]([NH:28][OH:29])=[O:14])=[N:10][CH:9]=[C:8]2[N:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:18]=[CH:19][C:7]=12)[CH3:2]
Reactant: NO
Reactant: CCO/C=C/c1c(C(=O)OCC)ncc2c1ccn2Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCO/C=C/c1c(C(=O)NO)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
To ethyl 4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.2 g, 0.54 mmol) in methanol (5 mL) were added hydroxylamine (1 mL, 50% in water, 15.2 mmol) and sodium hydroxide (0.0763 g, 1.9 mmol). The mixture was stirred at room temperature for 5 h, neutralized with 4N aq. HCl solution (0.48 mL, 1.9 mmol), and extracted with ethyl acetate. The organic extract was concentrated and recrystallized from ethyl acetate/ethyl ether/hexane to give the title compound (0.12 g, 62% yield). 1H NMR (DMSO-d6) 6; 11.76 (d, 1H, J=1.9 Hz), 8.88 (d, 1H, J=1.9 Hz), 8.60 (s, 1H), 7.83 (d, 1H, J=3.0 Hz), 7.31 (t, 2H, J=8.9 Hz), 7.22 (d, 1H, J=13.2 Hz), 7.05 (t, 2H, J=8.9 Hz), 6.82 (d, 1H, J=3.0 Hz), 6.66 (d, 1H, J=13.2 Hz), 5.54 (s, 2H), 3.96 (q, 2H, J=7.0 Hz), 1.28 (t, 3H, J=7.0 Hz). LCMS (APCI, M+H+): 356.1. Anal. (C19H18FN3O3) C, H, N. HPLC: 95% purity.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.C(O)(=O)C.[N+:32]([CH3:35])([O-:34])=[O:33].C([O-])(=O)C.[NH4+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:35][N+:32]([O-:34])=[O:33])[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (1.42 g, 3.79 mmol) was added acetic acid (12.6 mL), nitromethane (1.44 mL, 26.5 mmol), and ammonium acetate (0.731 g, 9.48 mmol) before it was stirred at 100° C. for 4 h. The reaction mixture was cooled to ambient temperature. The product crashed out with water, and was filtered, washed with water, and dried in a vacuum oven to give 2-(2-fluoro-4-(2-nitrovinyl)phenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine. MS (ESI) m/z: Calculated: 417.1; Observed: 418.4 (M++H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[OH-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17]>>[ClH:17].[ClH:1].[OH:20][CH:18]1[CH2:19][N:6]2[C:5](=[N:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=32)[CH2:4][NH:3][CH2:16]1
Reactant: ClCC1CO1
Reactant: NCc1nc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: OC1CNCc2nc3ccccc3n2C1
Reaction time: 3 h
Yield: 76 %

Procedure:
22 g. (0.1 moles) of 2-aminomethyl-benzimidazole dihydrochloride are suspended in 250 ml. of alcohol, and an alcohol solution of 12 g. (0.3 moles) of sodium hydroxide is added slowly to the cooled suspnesion. Thereafter 9.2 g. (0.1 moles) of epichlorohydrine are added to the mixture, and the reaction mixture is boiled for 3 hours under reflux. The mixture is cooled, the sodium chloride is removed by filtration, and the filtrate is evaporated to dryness under reduced pressure. The oily residue is dissolved in a mixture of acetone and alcohol, and the pH of the solution is adjusted to 3 with hydrochloric acid. The separated white, crystalline substance is filtered off, washed with a small amount of the above solvent, and dried. This way 20.9 g. (76%) of 2,3,4,5-tetrahydro-4-hydroxy-1H-(1,4)-diazepino[1,2-a]benzimidazole dihydrochloride are obtained; m.p.: 248°-250°C (heating rate: 4°C/min.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21](Cl)(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=1>>[Br:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:23])=[C:16]([F:25])[CH:15]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(F)c(Br)cc2F)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-bromo-2,5-difluorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (21.9 mg) with purity >90%. MS (pos) m/z 441.0, 443.0.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:30]1([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.CCCCCC.C(OCC)C>[C:30]1([CH2:36][C:37]([NH:39][C:40](=[O:41])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]5[CH2:27][CH2:26][CH2:25]5)[CH2:18][CH2:17]4)=[O:15])[CH:8]=3)=[CH:28][CH:29]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)cc1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 4-[2-(azetidin-1-yl) ethyl]piperazine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (36.3 mg) in N,N-dimethylformamide (1 ml) was added a solution of 0.25 M 2-phenylacetyl isocyanate in hexane (1.1 ml) under a nitrogen atmosphere, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (3.0 ml) and hexane (1.5 ml). The solid was filtered off and dried under aeration to provide the titled compound (28.6 mg, 56.0%) as white powder.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)/C=C\C(O)=O.[Cl:33][C:34]1[CH:53]=[CH:52][C:37]2[O:38][C:39]3[CH:51]=[CH:50][CH:49]=[CH:48][C:40]=3[C@@H:41]3[C@H:46]([NH2:47])[CH2:45][CH2:44][CH2:43][N:42]3[C:36]=2[CH:35]=1>C(Cl)Cl>[Cl:33][C:34]1[CH:53]=[CH:52][C:37]2[O:38][C:39]3[CH:51]=[CH:50][CH:49]=[CH:48][C:40]=3[C@@H:41]3[C@H:46]([NH:47][C:20](=[O:21])[C:19]4[CH:23]=[CH:24][C:16]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:17][CH:18]=4)[CH2:45][CH2:44][CH2:43][N:42]3[C:36]=2[CH:35]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
DIPEA (18.6 μL, 0.14 mmol) and 4-phenylbenzoyl chloride (15.2 mg, 0.07 mmol) were added to a solution of trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine maleate (9.6 mg, 0.02 mmol) in 1 mL of CH2Cl2. The resulting mixture was stirred for 18 h at room temperature. The organic layer was washed with 5% aqueous sodium bicarbonate and H2O, dried (Na2SO4) and evaporated. Additional chromatography on silica (elution with toluene/ethyl acetate 9:1→toluene/ethyl acetate 1:1) gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-4-phenylbenzamide (4.6 mg, 44%). Data: (m/z)=350 (M+H)+.
Reaction SMILES: [O-:1][P:2]([O-:5])([O-:4])=[O:3].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].Cl.[P:23](=O)(O)(O)[OH:24]>>[O:3]=[P:2]12[O:5][P:7]3([O:10][P:12]([O:15][P:23]([O:9]3)([O:4]1)=[O:24])(=[O:13])[O:1]2)=[O:8]
Reactant: O=P(O)(O)O
Reactant: O=P([O-])([O-])[O-]
Agent: Cl
Agent: [Ca+2]
Agent: [F-]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3

Procedure:
In the same manner as in Ex. 1-3, phosphate rock from Zin, Israel of the same analysis and particle size as before was heated at various temperatures and for various times. The treated rock was reacted with hydrochloric acid as before and in separate experiment with a sulphuric/phosphoric acid mixture and the colour of the liquid noted and organic and P2O5 content of the liquid obtained. The sulphuric/phosphoric acid was a mixture of 200 g of 20% P2O5 thermal phosphoric acid and enough 56% sulphuric acid to combine with 98% of the calcium content of the phosphate rock used, the amount of which was such as to contain 40 g P2O5. The specified amount of rock was mixed with stirring with 200 g of phosphoric acid at 60° C. When foaming ceased the sulphuric acid was added and the mixture stirred for 2 hrs at 70° C. to give a suspension of gypsum in phosphoric acid. The suspension was filtered hot and the filter cake washed three times with 50 cc cold tap water. All the filtrates were combined to give the product acid which was analysed for P2O5, total carbon and oxidizable carbon contents. The rock before and after the heating was also analysed for F. The results were as follows. (see Table 2). The Zin rock before heat treatment contained acid insoluble iron sulphide in amount of 250 ppm (expressed as S).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.C(N(CC)CC)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(c1ccccc1)N1CCN(c2ccc(Br)cc2)CC1
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
A 500 mL round-bottomed flask was charged with 1-(4-bromophenyl)piperazine (10.00 g, 41.5 mmol, Combi-Blocks, San Diego, Calif.) and 100 mL of CH2Cl2. To this was slowly added triethylamine (6.94 mL, 49.8 mmol) and benzenesulfonyl chloride (6.15 mL, 47.7 mmol). After 15 min at room temperature, the mixture was diluted with water (100 mL) and layers were separated. The organics were dried (MgSO4) and concentrated. The resulting solid was slurried with diethyl ether (200 mL) to give 1-(4-bromophenyl)-4-(phenylsulfonyl)piperazine (15.00 g) as a white solid.
Reaction SMILES: C(N[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19](O)[CH2:20][N:21]([CH3:25])[C:22](=[O:24])[CH3:23])CCCCCCC.[H-].[Na+].BrCCCCCCCCCC=C.CNC(=O)C>CS(C)=O.O>[CH3:25][N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH2:10])[C:22](=[O:24])[CH3:23]
Reactant: CCCCCCCCNCCCCCCCCCC(O)CN(C)C(C)=O
Agent: C=CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CNC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCCN(C)C(C)=O
Reaction time: 8 h
Yield: 57 %

Procedure:
This example illustrates a synthesis of 1-Octylamino-10-hydroxy-11-(N-methylacetamido)undecane (compound no. 77). Sodium hydride (0.56 g, 23 mmol) was added to a solution of 1-bromo-10-undecene (5.4 g, 23 mmol) and N-methylacetamide (91.7 g, 23 mmol) in DMSO (40 mL). After 8 hours, the reaction was complete and the mixture added to water (100 mL) and extracted with dichloromethane (3×100 mL). The combined extracts were washed with water (70 mL) and saturated aqueous salt solution (70 mL), and dried over sodium sulfate. The solvent was evaporated under vacuum to give a yellow residue, which was chromatographed (silica/ethyl acetate), yielding 2.95 g of 1-(N-methylacetamido)-10-undecene as a colorless oil (57% yield).