Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][C:35]=1[C:43]([F:46])([F:45])[F:44].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.C(#N)C.CCOC(C)=O>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:20])([F:21])[F:19])[CH:12]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:30])([F:31])[F:32])[CH:23]=2)[C@@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:39])=[CH:36][C:35]=1[C:43]([F:44])([F:45])[F:46]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: NC(c1cccc(OC(F)(F)F)c1)(c1cccc(OC(F)(F)F)c1)[C@@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC(c1cccc(OC(F)(F)F)c1)(c1cccc(OC(F)(F)F)c1)[C@@H](O)c1ccccc1)c1ccc(F)c(C(F)(F)F)c1
Yield: 15 %

Procedure:
A solution of (S)-2-amino-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol (44 mg, 0.096 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (20 mg, 0.096 mmol), EDCI (28 mg, 0.14 mmol), HOBT (14 mg, 0.096 mmol) and a catalytic amount of DMAP in acetonitrile (3 mL) was stirred for 24 h at rt. The reaction mixture was diluted with EtOAc and washed successively with 1 N HCl, 1 N NaOH, sat. NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC Shimadzu-YMC Sunfire 5μ column, 30×100 mm eluting with 50-100% MeOH (90% in H2O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (S)-4-Fluoro-N-(2-hydroxy-2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 311) was isolated as a colorless film (10 mg, 15% yield). HPLC: RT=4.143 minutes (Phenomenex Luna C18 5 u column eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient monitoring at 220 nm). LCMS: [M+H] 648.0 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.23 (m, 1H), 7.37-6.9 (m, 15H), 5.41 (s, 1H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29].Cl>O.C(O)C>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: OCCCCCCCl
Reactant: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C)COc1ccc(-c2ccc(OCCCCCCO)cc2)cc1

Procedure:
4.5 g of KOH and 15 g of 4-hydroxy-4'-(2-methylbutoxy)-biphenyl are dissolved in 150 ml of a 1:1 water/ethanol mixture, the solution is raised to the boil and 9 g of 6-chloro-1-hexanol are slowly added dropwise, whilst stirring, after which the batch is refluxed for about 10 hours. When the reaction solution has cooled, it is acidified with HCl and the product is extracted with CHCl3 in a separating funnel. The CHCl3 is then stripped off and the crude product is recrystallized from ethanol (melting point 118° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:26]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1OC(C)C
Temperature: 25 °C

Procedure:
A solution of 4-(benzyloxy)-2-isopropoxybenzaldehyde (698) (480 mg, 1.776 mmol) and (carbethoxymethylene)triphenylphosphorane (1.1 eq.) in toluene was heated at 100° C. overnight. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford (E)-ethyl 3-(4-(benzyloxy)-2-isopropoxyphenyl)acrylate (699).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].Cl>C1COCC1>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:9]1=[O:10]
Reactant: Nc1ccccc1S
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2s1
Reaction time: 12 h

Procedure:
To 2-amino-benzenethiol (10 g, 79.9 mmol) in THF (200 mL) at room temperature was added carbonyldiimidazole (14.3 g, 87.9 mmol) and the reaction solution stirred for 12 hours. Upon disappearance of starting material, the reaction solution was poured into 1N HCl (125 mL) and extracted with ethyl acetate (125 mL). The organic layer was dried over sodium sulfate and concentrated to give 1,3-benzothiazol-2(3H)-one as a white solid. MS (ES) m/z 152.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:35])[N:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])[C:21]4[N:22]3[CH:25]=[CH:26][N:27]=4)=[CH:17][N:16]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:19](=[O:35])[N:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])[C:21]4[N:22]([CH:25]=[CH:26][N:27]=4)[C:23]=3[N:24]=2)=[CH:10][CH:9]=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2ncc3c(=O)n(-c4ccccc4Cl)c4nccn4c3n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Nc2ncc3c(=O)n(-c4ccccc4Cl)c4nccn4c3n2)cc1

Procedure:
A mixture of Example 56A (0.260 g, 0.516 mmol) and trifluoroacetic acid (0.397 mL, 5.16 mmol) in CH2Cl2 (5 mL) was stirred at 40° C. for 4 hours. The reaction mixture was concentrated and purified by HPLC (see protocol in Example 1F) to provide the title compound as a trifluoroacetic acid salt. The salt was treated with saturated aqueous NaHCO3 followed by filtration and drying to give a free base form of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 3.96 (s, 2H), 7.09 (d, J=1.8 Hz, 1H), 7.38-7.23 (m, 2H), 7.66-7.52 (m, 3H), 7.76-7.69 (m, 1H), 7.96-7.91 (m, 3H), 9.16 (s, 1H), 10.73-10.68 (m, 1H). MS (ESI+) m/z 404.2 (M+H)+.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]([O:26][C:27]([O:29][CH3:30])=[O:28])[CH2:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[N:21][C:22]([O:24][CH3:25])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:31]>C(O)C>[C:1]1([O:11][CH2:12][CH:13]([O:26][C:27]([O:29][CH3:30])=[O:28])[CH2:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2([Cl:31])[NH:21][C:22]([O:24][CH3:25])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cl
Reactant: COC(=O)N=c1ccccn1CC(COc1cccc2ccccc12)OC(=O)OC
Solvent: CCO
Product: COC(=O)NC1(Cl)C=CC=CN1CC(COc1cccc2ccccc12)OC(=O)OC

Procedure:
18 Grams of 3-(1-naphthoxy)-1-(2-methoxycarbonylimino-1,2-dihydro-1-pyridyl)-2-methoxycarbonyloxypropane were dissolved in about 50 ml of absolute ethanol. Concentrated hydrochloric acid was added dropwise until the pH was 1.0. The mixture was heated until a homogeneous solution was obtained and additional hydrochloric acid was added to bring the pH to 1.0. The solvent was evaporated under vacuum and the residual oil was dissolved in 25 milliliters of hot isopropyl alcohol. The product which crystallized on cooling was collected on a filter, washed with isopropyl alcohol, and dried to yield 3-(1-naphthoxy)-1-(2-chloro-2-methoxycarbonylamino-1,2-dihydro-1-pyridyl)-2-methoxycarbonyloxypropane. M.P. 133°-135° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:24][O:25][CH2:26][CH2:27][O:28][CH:29]=[CH2:30].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:24][O:25][CH2:26][CH2:27][O:28][CH:29]=[CH2:30])=[O:7]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(CCCO)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Product: C=COCCONC(=O)c1ccc(F)c(F)c1Nc1ccc(CCCO)cc1F
Yield: 46 %

Procedure:
The title compound was prepared from reaction of 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]benzoic acid with 1-[2-(aminooxy)ethoxy]ethylene and DMT-MM by the general procedure of Example 6, Step B, then purified by column chromatography on silica gel (20% EtOAc/PE as eluant) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]-N-[2-(vinyloxy)ethoxy]benzamide as a white solid (46%), which was employed directly in the next step. 1H NMR [400 MHz, (CD3)2SO] δ 11.93 (br s, 1 H), 8.79 (br s, 1 H), 7.44–7.38 (m, 1 H), 7.14–7.05 (m, 1H), 7.04 (dd, J=12.6, 1.6 Hz, 1 H), 6.89 (dd, J=8.2, 1.6 Hz, 1 H), 6.82 (ddd, J=8.7, 8.7, 4.4 Hz, 1 H), 6.50 (dd, J=14.3, 6.7 Hz, 1 H), 4.45 (t, J=5.1 Hz, 1 H), 4.18 (dd, J=14.3, 1.9 Hz, 1 H), 4.06–4.01 (m, 2 H), 3.98 (dd, J=6.6, 1.9 Hz, 1 H), 3.89–3.82 (m, 2 H), 3.42–3.35 (m, 2 H), 2.56 (t, J=7.7 Hz, 2 H), 1.72–1.64 (m, 2 H). LCMS (APCI−) 409 (M−H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1F.[Cl:18]C1C=CC(C=O)=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:5]2[CH:4]=[CH:3][CH:2]=[C:7]([Cl:18])[N:6]=2)=[CH:12][CH:13]=1
Reactant: Fc1nc(NCc2ccc(Cl)cc2)ccc1Br
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1ccc(CNc2cccc(Cl)n2)cc1

Procedure:
To 6-chloro-pyridin-2-ylamine (537, 5.60 g, 0.0436 mol) in acetonitrile (300 mL) were added 4-chlorobenzaldehyde (40, 6.7 g, 0.048 mol), trifluoroacetic acid (13 mL, 0.17 mol) and triethylsilane (21 mL, 0.13 mol). The reaction was heated to reflux for 4 hours, then concentrated, poured into water, extracted with ethyl acetate, and washed with sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The filtrate was purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (538, 6.5 g, 59%). MS (ESI) [M+H+]+=255.1.
Reaction SMILES: O.[I-:2].[I-].[I-].[I-].[CH2:6]([C:8]1[C:21]2[C:12](=[S+:13][C:14]3[C:19]([N:20]=2)=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)[CH3:7].[CH2:23]([C:25]1[C:38]2[C:29](=[S+:30][C:31]3[C:36]([N:37]=2)=[C:35]([CH3:39])[CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=1)[CH3:24].[CH2:40]([C:42]1[C:55]2[C:46](=[S+:47][C:48]3[C:53]([N:54]=2)=[C:52]([CH3:56])[CH:51]=[CH:50][CH:49]=3)[CH:45]=[CH:44][CH:43]=1)[CH3:41].C(C1[C:72]2C(=[S+]C3[C:70]([N:71]=2)=C(C)C=CC=3)C=CC=1)C.C(Cl)(Cl)Cl>>[I-:2].[I-:2].[I-:2].[CH2:6]([C:8]1[C:21]2[C:12](=[S+:13][C:14]3[C:19]([N:20]=2)=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:10]([N:37]([CH3:38])[CH3:36])[CH:9]=1)[CH3:7].[CH2:40]([C:42]1[C:55]2[C:46](=[S+:47][C:48]3[C:53]([N:54]=2)=[C:52]([CH3:56])[CH:51]=[CH:50][CH:49]=3)[CH:45]=[C:44]([N:71]([CH3:72])[CH3:70])[CH:43]=1)[CH3:41].[CH2:23]([C:25]1[C:38]2[C:29](=[S+:30][C:31]3[C:36]([N:37]=2)=[C:35]([CH3:39])[CH:34]=[CH:33][CH:32]=3)[CH:28]=[C:27]([N:20]([CH3:21])[CH3:19])[CH:26]=1)[CH3:24]
Reactant: CCc1cccc2[s+]c3cccc(C)c3nc12
Agent: [I-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1cc(N(C)C)cc2[s+]c3cccc(C)c3nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred mixture of 1-ethyl-9-methylphenothiazin-5-ium tetraiodide hydrate (383 mg, 0.5 mmol) in anhydrous CHCl3 (20 mL) dimethylamine (0.5 mL, 1.0 mmol, 2 m solution in THF) was added drop wise over 4 h. The resulting mixture was stirred at room temperature overnight, concentrated to dryness.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[C:10]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(Cl)cc2)nc1Cl

Procedure:
A mixture of the product from Step 1 (54 g, 0.26 mol), p-chlorophenol (31.7 g, 0.25 mol) and cesium carbonate (101.4 g, 0.31 mol) in anhydrous DMF (1.0 L) was stirred at 25° C. for about 2 h or until less than 5% of the starting material remained. The reaction mixture was then poured into water (2.5 L) and extracted with ethyl acetate (2×800 mL). The organic layer was washed with water (2×300 mL) and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel eluting with 7:1 hexane:ethyl acetate to afford the title product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(O[N:51]1[N:59]=[N:58][C:53]2[CH:54]=[CH:55][CH:56]=[N:57][C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:58]1[C:53]2[C:52](=[N:57][CH:56]=[CH:55][CH:54]=2)[N:51]([O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[N:59]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)On2nnc3cccnc32)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with HATU to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester. MS (ES+) m/z calcd. for C36H32Cl2F2N7O4: [(M+H)+]: 734. found: 734.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:41]1([CH2:47][CH2:48][NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:44]3[CH2:45][CH2:46][N:41]([CH2:47][CH2:48][NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:42][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-methanesulfonamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 739.3 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].Br[CH2:25][C:26]([NH2:28])=[O:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[NH2:28][C:26](=[O:27])[CH2:25][N:19]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: NC(=O)CBr
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)OCc2ccccc2)cc1N(CC(N)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Benzyl 4-methoxy-3-(methylsulfonamido)benzoate (200 mg, 0.596 mmol) was dissolved in DMF (2 ml). 2-bromoacetamide (247 mg, 1.789 mmol) and K2CO3 (165 mg, 1.193 mmol) were added, and the reaction was stirred at RT overnight. The reaction mixture was diluted with water and filtered. The precipitate was washed with water and dried in the vacuum oven to give benzyl 3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoate (220 mg, 94% yield).
Reaction SMILES: [CH:1]([C:4]1[C:5]([OH:18])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)([CH3:3])[CH3:2].Br[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>>[CH:1]([C:4]1[C:5]([O:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[CH:6][C:7]2[C:8]([CH3:16])([CH3:17])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(Br)cc1
Product: COC(=O)c1ccc(Oc2cc3c(cc2C(C)C)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 1(a) above, by the reaction of 2 g (8.1 mmol) of 3-isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthol with 1.45 g (6.7 mmol) of methyl 4-bromo-benzoate, 840 mg (33%) of the expected methyl ester of melting point 115-6° C. were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH:21]([CH3:23])[CH3:22])[CH:12]=3)[CH2:7]2)[CH2:5][CH2:4][CH2:3]1.O.NN>C(O)C.[Pd]>[CH3:1][N:2]1[C:6]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:20][CH:21]([CH3:23])[CH3:22])[CH:12]=3)[CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)Oc1cc(N2CCC3(CCCN3C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(N2CCC3(CCCN3C)C2)ccc1N
Temperature: 80 °C
Yield: 97.3 %

Procedure:
A mixture of 160 mg of 1-methyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane, 301 mg of hydrazine hydrate and 27 mg of 10% palladium-on-carbon in 30 ml of ethanol is heated at 80° C. (bath) for 2 h. The mixture is filtered and the filtrate is concentrated under vacuum, so as to obtain 141 mg of 4-(1-methyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)aniline in the form of a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:27][CH3:28])[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44]>CCN(CC)CC>[CH3:28][O:27][C:4]1[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]2[C:11](=[C:2]([NH:1][CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]3[C:38](=[O:39])[C:37]4=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]4[C:35]3=[O:44])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCCCc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCCCc1ccccc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(7-phenylheptoxy) quinoline [Example 1c] (9.2 g, 0.024 mol) and 4-bromo-1-phthalimidopentane (BPP) (15 g, 0.05 mol) was heated at 120°-125° C. while Et3N (5 ml) was added in small portions. After 3 h at 120°-125° C., second portions of BPP (7.5 g) and Et3N (2.5 ml) were added and heating was continued for 4 h. Third portions of BPP (3 g) and Et3N (1 ml) were introduced, and heating was continued for 2 h. The reaction was allowed to cool and extracted with Et2O (total, ca. 500 ml). The extract was treated with carbon and then with saturated ethereal hydrogen chloride (300 ml). The resulting dark red semi-solid mass was separated and basified with Et2O--Et3N. Concentration of the ethereal solution left 11.5 g (81 %) of brown oil which was dissolved in CHCl3, placed on a silica gel column (200 g) and eluted with CHCl3. The first six eluates (75 ml each) were combined and concentrated to give 10.9 grams of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-(7-phenylheptoxy) quinoline which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:16])=[C:9](\[CH3:15])/[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:16])=[C:9](\[CH3:15])/[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(C)=C(\C)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(CO)=C(/C)c1ccc(Br)cc1

Procedure:
(E)-Ethyl 3-(4-bromophenyl)-2-methyl-but-2-enoate (2.83 g, 9.99 mmol) was reduced with DIBAL-H by a procedure analogous to that described in example 52b to give (E)-3-(4-bromophenyl)-2-methyl-but-2-en-1-ol as a colourless oil; 1.82 g (75%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([Cl:10])[N:3]=1.[CH:11]([Mg]Br)=[CH2:12].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:11]=[CH2:12])[C:5]([O:8][CH3:9])=[C:4]([Cl:10])[N:3]=1
Reactant: C=C[Mg]Br
Reactant: COc1cnc(Cl)nc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: C=Cc1nc(Cl)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of commercially available 2,6-dichloro-5-methoxy pyrimidine (100 grams (g), 0.55 moles (mol)) in dry tetrahydrofuran (THF) was added, dropwise, 1 molar (M) vinyl magnesium bromide in tetrahydrofuran solvent (124 g, 0.94 mol) over one hour (h) at room temperature. The mixture was then stirred for 4 h at room temperature. Excess Grignard reagent was quenched by addition of acetone (200 milliliters (mL)) while the temperature of the mixture was maintained at a temperature below 20° C. Thereafter, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (151 g, 0.67 mol) was added at once and stirred overnight. A yellow solid precipitated out. The solid was filtered and washed with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure and the resulting crude compound was diluted with ethyl acetate (2 liters (L)). The resulting undissolved, dark, semi-solid was separated by filtration using ethyl acetate. It was further concentrated under reduced pressure to provide a crude compound, which was purified by column chromatography. The compound was eluted with 5% to 10% ethyl acetate in hexane mixture to provide the title compound (70 g, 60%): mp 60-61° C.; 1H NMR (CDCl3) δ 3.99 (s, 3H), 5.85 (d, 1H), 6.75 (d, 1H), 6.95 (dd, 1H).