Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].C(Cl)(=O)[C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13](=[O:14])[C:15]3[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=3)=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Solvent: Cc1ccccc1C
Product: CC1(C)C(=O)NC(=O)c2c1ccc(NC(=O)c1ccccc1)c2[N+](=O)[O-]
Yield: 67.8 %

Procedure:
43.8 gm of 4,4-dimethyl-7-acetamino-8-nitro-2H,4H-isoquinoline-1,3-dione were admixed with 200 gm of xylene with 104 gm of benzoyl chloride, and the mixture was refluxed for 10 hours while stirring. After cooling, the reaction mixture was suction-filtered, and the filter cake was washed with toluene and petroleum ether, yielding 36 gm (68% of theory) of 4,4-dimethyl-7-benzoylamino-8-nitro-2H,4H-isoquinoline-1,3-dione, m.p. above 270° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.S(Cl)([Cl:16])(=O)=O.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:16])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Oc1ccc2cc(Br)ccc2c1Cl
Reaction time: 2 h

Procedure:
The solution of 6-bromo-2-naphthol (10.0 g, 0.045 mol) in chloroform (100 mL) was added sulfuryl chloride (6.4 mL, 0.09 mol). The mixture was stirred at reflux for 0.5 hour then at room temperature for 2 hours. Water (50 mL) was added and the organic phase was washed with water then solvent evaporated. The solid was crystallized from hexane and air dried to give the title compound as a solid, mp 103-105° C. Mass spectrum (−ES, [M−H]−) m/z 255, 257, 259. 1HNMR (500 MHz, DMSO-d6): δ10.63 (s, 1H), 8.15 (d, 1H, J=1.8 Hz), 7.95 (d, 1H, J=9.0 Hz), 7.7 (d, 1H, J=9 Hz), 7.68 (dd, 1H, J=9.0, 1.8 Hz), and 7.32 ppm (d, 1H, J=8.85 Hz). Elemental Analysis for C10H6BrClO: Calculated: C, 46.64; H, 2.35; N, 0.00. Found: C, 46.69; H, 2.35; N, 0.00.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccccc1OC
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccccc1OC

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-1-(2-methoxyphenyl)-5-hydroxyindole-3-carboxylic acid ethyl ester (139 mg, 0.35 mmol, see step (b) Example 11) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 120 mg (63%).
Reaction SMILES: O1C2C=CC=CC=2OC[CH:2]1CN1CCCC(COC)(C)C1.[O:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH2:24][CH:23]1[CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][C:35]([C:40]([OH:43])([CH3:42])[CH3:41])([CH3:39])[CH2:34]1>>[O:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH2:24][CH:23]1[CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][C:35]([C:40]([O:43][CH3:2])([CH3:42])[CH3:41])([CH3:39])[CH2:34]1
Reactant: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Reactant: CC(C)(O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Product: COC(C)(C)C1(C)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared according to the procedure described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine except that 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]propan-2-ol was used instead of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([N:25]4[CH2:30][CH2:29][S:28][CH2:27][CH2:26]4)=[O:23])=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: C1CSCCN1
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)N1CCSCC1
Yield: 37 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using thiomorpholine instead of 4-aminotetrahydropyran, to the title compound (32 mg, 37%) which was obtained as a colourless gum after purification by chromatography (silica, heptane:ethyl acetate 1:0 to 0:1 then dichloromethane:methanol 1:0 to 95:5). MS: m/e=433.2 [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[CH:27]=[C:26]([NH:28]N)[CH:25]=[CH:24][N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:25]=[CH:24][N:23]=1
Reactant: NNc1ccnc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccnc(Cl)c1
Yield: 9 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2-chloro-4-hydrazinopyridine according to the method described for Example 1 in 9% yield. MS: M=350.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:5][C:6](=[O:26])[C@@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O.[ClH:32].[H][H]>CO.[Pd]>[ClH:32].[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:5][C:6](=[O:26])[C@@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:8]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1ccccc1

Procedure:
A solution of 7 g. (0.016 mol) of Nα -benzyloxycarbonyl-D-phenylalanyl-L-leucine methyl ester in 120 ml. of methanol is treated with 6.12 ml. of 2.68N hydrogen chloride in methanol and reduced with hydrogen and 500 mg. of 10% palladium-on-carbon at atmospheric pressure. The reaction is monitored by thin layer chromatography. The mixture is filtered to separate the catalyst and the solution evaporated; 5.4 g. as a glass; [α]D23 -82.5° (c 1.02, methanol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13](=[O:21])[O:12]1.C(O)(=O)C>CCOC(C)=O>[OH:12][CH2:11][C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:14][C:13]([N:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:21]
Reactant: O=C1Cc2ccccc2CO1
Reactant: CNNC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(NC(=O)OC(C)(C)C)C(=O)Cc1ccccc1CO
Temperature: 100 °C

Procedure:
N-(t-Butoxycarbonyl)-N′-methylhydrazine (100 mmol) (Lenman, et al., J. Chem. Soc. Perkin Trans., 1997, 16, 2297-2312; Dutta, et al., J. Chem. Soc. Perkin Trans., 1986, 1655-1664) was added to 3-isochromanone (7.4 g, 50 mmol) (Cheng, et al., J. Heterocyclic Chem., 1995, 32, 73) in a sealed tube followed by 0.2 mL of acetic acid and heated for 12 h at 100° C. The reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL),1 M HCl (50 mL), brine (50 mL) and dried (Na2SO4). The desired alcohol 2-[2-[2-(Hydroxymethyl)phenyl]-1-oxoethyl]-2-methylhydrazinecarboxylic acid, 1,1-dimethylethyl ester was purified by flash chromatography (silica) using 50% EtOAc in hexane as eluent. MS (ESI) 295 (M+H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(C)C.Br[CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1>C1C=CC=CC=1>[Br:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: Brc1ccc(OC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)O
Product: Brc1ccc(OC2CCN(CCc3c[nH]c4ccccc34)CC2)cc1
Reaction time: 22 h

Procedure:
A mixture of 8.1 g of 4-(p-bromophenoxy)piperidine hydrochloride, 12.6 g of potassium carbonate and 60 ml. of isopropanol is stirred and refluxed for one hour. A solution of 6.5 g of 3-(2-bromoethyl)indole in 15 ml. of isopropanol is then added. Stirring and refluxing is continued for 22 hours, and the reaction mixture is filtered hot. A yellow oil separates in the cooled filtrate and the supernatant isopropanol is decanted from the oil. The isopropanol is diluted with ether, causing the unreacted 4-(p-bromophenoxy)piperidine to separate. After filtration, the isopropanol is removed under reduced pressure to give a yellow oil. The oil is permitted to stand for 3 weeks during which time it solidifies to a soft brown solid. Trituration of the solid with benzene affords yellow crystals, which are recrystallized from acetonitrite to give slightly yellow cubes of 3-{2-[4-(p-bromophenoxy)piperidyl]ethyl]-indole, m.p. 132°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:31]2)[CH2:26][O:25]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 4 °C
Reaction time: 5 h
Yield: 88.1 %

Procedure:
To a 200-L glass-lined reactor was charged with 46.3 kg of dichloromethane (DCM). To the reactor was added additional 112.0 kg of dichloromethane followed by 11.9 kg (36.8 mol) of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methylpentanoic acid and 8.0 kg (40.6 mol) of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine. With agitation, to the mixture was added 0.44 kg of 1-hydroxybenzotriazole. After cooling to 4° C., 14.0 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added in 4 portions (5.0 kg+3.1 kg+3.8 kg+2.1 kg) over 3 h while maintaining the batch temperature at 4-10° C. The mixture was agitated at 4-12° C. for additional 5 h. HPLC analysis at 2.5 h indicated the completion of the reaction. The mixture was transferred into a 500 L glass-line reactor. After adjusting the batch temperature to below 10° C., the reaction was quenched by adding 119.0 kg of water. The aqueous phase was separated and the organic solvent was removed by distillation in vacuo to a final volume of ca. 30 L. To the residue was added 106.0 kg of ethyl acetate. The mixture was stirred for 30 min, cooled to 0-10° C., and washed with 5 wt % citric acid solution, 10 wt % sodium carbonate solution and 2.5 wt % sodium chloride solution. The solvent was removed by distillation in vacuo at 18-30° C. to a final volume of ca. 30 L. To the residue solution was added 64.7 kg of n-heptane over 2.5 h. After adjusting the batch temperature to 0-5° C. the mixture was agitated for 4.5 h. The solids were collected in a Nutsche filter, rinsed with 16.2 kg of n-heptane, dried with nitrogen flow at 40-45° C. for 20 h to afford 17.2 kg (88.1% yield) of ((S)-2-[4-(2-Chlorophenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide. 1H NMR (300 MHz, DMSO-d6, ethanol removed) δ ppm 0.90 (d, J=6.4 Hz, 3 H), 0.94 (d, J=6.4 Hz, 3 H), 1.05 (br. s., 3 H), 1.06 (br. s., 3 H), 1.36-1.64 (m, 2 H), 1.68-1.84 (m, 1 H), 3.89 (s, 2 H), 4.20 (d, J=18.4 Hz, 1 H), 4.62 (d, J=18.4 Hz, 1 H), 4.68 (s, 1 H), 4.78 (s, 1 H), 4.90 (dd, J=10.7, 4.7 Hz, 1 H), 6.44 (d, J=2.1 Hz, 1 H), 7.37 (td, J=7.8, 1.8 Hz, 1 H), 7.46 (td, J=7.8, 1.2 Hz, 1 H), 7.50-7.56 (m, 2 H), 7.66 (dd, J=7.8, 1.2 Hz, 1 H), 10.81 (s, 1 H).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:3])=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:41][O:40][C:38]1[CH:39]=[C:34]([NH:33][C:31](=[O:32])[CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([NH:23][C:1]([C:4]3[C:5]([C:15]4[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:22])=[N:6][O:7][C:8]=3[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:3])[CH:25]=2)[CH:35]=[C:36]([O:44][CH3:45])[C:37]=1[O:42][CH3:43]
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1ccccc1
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)c3c(-c4c(F)cccc4Cl)noc3-c3ccccc3)c2)cc(OC)c1OC
Reaction time: 14 h
Yield: 64.5 %

Procedure:
To a solution of 4-carboxy-5-phenyl-3-(2-chloro-6-fluorophenyl)isoxazole (0.135 g, 0.425 mmol) and 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (0.129 g, 0.408 mmol) in dichloromethane (5 ml) was added EDCI (0.082 g, 0.51 mmol) and DMAP (0.062 g, 0.51 mmol) and stirred for 14 h. The mixture was applied to a silica gel chromatography column. Elution with hexanes and ethyl acetate (gradient) gave the title compound (0.162 g, 64%).
Reaction SMILES: [OH-].[Na+].Cl.[N:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH2:10][S:11][C:12](=N)N.BrC[CH2:17][CH2:18][Cl:19]>O>[Cl:19][CH2:18][CH2:17][CH2:12][S:11][CH2:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][N:4]=1
Reactant: N=C(N)SCc1cnccn1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1cnccn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (39 cc) is added dropwise, in the course of 15 minutes and at a temperature of about 10° C., to a solution of 2-(pyrazinylmethyl)-isothiourea monohydrochloride (77.6 g) in distilled water (250 cc). After heating for 30 minutes at 70° C. and then cooling to 15° C., a 10 N aqueous solution of sodium hydroxide (47 cc) and then 1-bromo-3-chloropropane (66.5 g) are added and stirring is continued for 15 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (280 cc in total). The organic extracts are combined, washed twice with distilled water (200 cc in total), dried over anhydous sodium sulphate and filtered. The solution obtained is poured onto neutral silica gel (80 g) contained in a column of diameter 2.7 cm; the column is then eluted with methylene chloride (900 cc). The first fraction (300 cc) is discarded; the second fraction (600 cc) is collected and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. Pyrazinylmethyl 3-chloropropyl sulphide (59 g) is thus obtained in the form of a yellow-orange oil.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[BrH:13]>C1CCCCC1.C(OCC)C>[Br:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: OCCCCCCCCCCO
Reactant: Br
Solvent: CCOCC
Solvent: C1CCCCC1
Product: OCCCCCCCCCCBr
Temperature: 30 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
87.8 g (0.50 mol) of 1,10-decanediol, 165.1 g of 48% strength hydrobromic acid and 2.5 l of high-boiling petroleum ether (b.p. 100-140° C.) were heated under reflux with vigorous stirring for 4 hours. A further 80.0 g of 48 strength hydrobromic acid were added, and the mixture was boiled for 5 hours. After cooling to 30° C., the phases were separated. The organic phase was washed first with a solution of 100 g of Na2CO3 in 500 ml of water and then with 2×500 ml of water. Removal of the solvent was followed by chromatography on 700 g of silica gel. The byproduct 1,10-dibromodecane was eluted with cyclohexane/diethyl ether (20:1). Chromatography with cyclohexane/diethyl ether (2:1) afforded 103.9 g (0.44 mol, 87%) of 10-bromo-1-decanol.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:6])[CH:2]=[CH2:3].[CH:25](N(C(C)C)CC)(C)C.CI>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][C:19]1=[O:24])=[O:6])[CH:2]=[CH2:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCNCC1=O
Solvent: ClCCl
Solvent: CI
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCN(C)CC1=O
Reaction time: 12 h

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-piperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (6.37 g) in dichloromethane (60 ml) were added N,N-diisopropyl-N-ethylamine (3.38 ml) and methyl iodide (1.64 ml) under ice cooling with stirring, and the mixture was allowed to stay in a refrigeration for 12 hours. The mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of ethyl acetate, methanol and isopropylamine (10:1:0.3 v/v/v) to give (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-4-methylpiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (3.19 g).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]([OH:43])[CH2:21][NH:22][C:23]([CH3:42])([CH3:41])[CH2:24][CH2:25][N:26]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]([CH2:38][CH3:39])([CH2:36][CH3:37])[O:28][C:27]2=[O:40])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:38]([C:29]1([CH2:36][CH3:37])[O:28][C:27](=[O:40])[N:26]([CH2:25][CH2:24][C:23]([NH:22][CH2:21][CH:20]([OH:43])[C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:19])[NH:16]3)([CH3:41])[CH3:42])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]1=2)[CH3:39]
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3[nH]c(=O)ccc23)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(O)cc3[nH]c(=O)ccc23)c2ccccc21

Procedure:
A suspension of 1-{3-[2-(7-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one (152 mg, 0.338 mmol) and Pd/C (10%) (40 mg) in MeOH (12 mL) is hydrogenated at room temperature (RT) and 1 bar hydrogen pressure for 4 hours. The catalyst is filtered off through CELITE® filter aid and washed with MeOH (5 mL). The organic phase is evaporated down, the residue is triturated with EtOAc and the precipitate formed is filtered off and dried in vacuo. Yield: 76 mg (46%); Rf=0.3 (silica gel, dichloromethane/MeOH/saturated aqueous ammonia 90:10:0.5); ESI-MS: [M+H]+=494.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([NH2:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:51](Cl)([O:53]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:39])([F:40])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:14][N:15]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=3[O:36][CH3:37])[C:51](=[O:53])[NH:38]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)NC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine (125.2 mg, 0.217 mmol) in CH2Cl2 (30 mL) was cooled to 0° C. and DIPEA (227 μL, 1.30 mmol) was added. Next, triphosgene (32.2 mg, 0.109 mmol) was added. The reaction was stirred at 0° C. for 45 minutes and then poured into saturated NaHCO3 (20 mL). The mixture was extracted with EtOAc (100 mL) and the organic layer was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography with 40% EtOAc/hexanes to afford 4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one. Rf=0.22 (40% EtOAc/hexane). LCMS=605.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) (atropisomers present in 1:1 ratio; doubling of some peaks observed) δ 7.83 (s, 1H), 7.78 (s, 2H), 7.55-7.62 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.22 (m, 1H), 6.94 (s, 1H), 6.88 (d, J=8.3 Hz, 1H), 5.33 & 5.24 (2 singlets, 1H), 4.80-4.88 (m, 1H), 4.00-4.61 (m, 2H), 3.72 & 3.70 (2 singlets, 3H), 3.55-3.59 (m, 1H), 2.83-2.93 (m, 2H), 1.17-1.23 (m, 6H).