Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OP(O)(O)=O.[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]2[C:36](=O)[CH2:35][N:34]([CH3:38])[C:33]2=[O:39])=[CH:23][CH:22]=1>O>[Cl:20][C:21]1[CH:41]=[CH:40][C:24]2[O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[C:33](=[O:39])[N:34]([CH3:38])[CH2:35][C:36]=3[C:23]=2[CH:22]=1
Reactant: CN1CC(=O)C(c2ccccc2Oc2ccc(Cl)cc2)C1=O
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CN1CC2=C(C1=O)c1ccccc1Oc1ccc(Cl)cc12
Reaction time: 8 h
Yield: 57.9 %

Procedure:
P2O5 (90 grams) was added in portions to H3PO4 (90 grams) while maintaining the temperature below 140° C. The mixture was heated at 115° C. for 1.5 hour, whereupon 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine-2,4-dione (XI) (30 grams; 95 mmol) was added. The resulting mixture was stirred for 4 days at 115° C. to 130° C. with extra P2O5 (in total 5 portions of 5 grams each were added). The mixture was poured into water (200 ml) and the resulting precipitate was stirred overnight. The mixture was extracted with dichloromethane (250 ml) and washed with sat. NaHCO3 (pH=7). After drying on magnesium sulphate the solvent was removed under vacuum. The resulting crude product was dissolved in methanol (520 ml) at 70° C. Following removal of part of the methanol by evaporation the product crystallized. The mixture was stirred overnight at −12° C. The crystals were filtered and dried to provide 5-chloro-2,3-dihydro-2-methyl-1H-dibenz [2,3;6,7]oxepino[4,5-c]pyrrol-1-one (VI) (16.4 grams, 55 mmol; 58%), purity according to GC 92%. 1H-NMR (400 MHz, CDCl3): 3.2 (s, 3H), 4.3 (s, 1H), 3.8 (m, 1H), 7.2-7.4 (m, 6H), 8.2 (dd, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[N:16]/[OH:17])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[N:16]/[O:17][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:38][CH:39]=2)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)/C(=N\O)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
Sodium hydride (60% in oil, 368 mg) was added under a nitrogen atmosphere to a solution of ethyl Z-2-(4-bromophenyl)-2-hydroxyiminoacetate (2.50 g) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (3.03 g) in N,N-dimethylformamide (25 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (12 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl Z-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (3.12 g, yield 61%) as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:11][CH:12]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Yield: 103 %

Procedure:
To a suspension of 318 (10 g, 22.05 mmol) in EtOH (216 ml) and water (108 ml) was added iron powder (10.47 g, 187 mmol) and ammonium chloride (1.015 g, 18.97 mmol). The mixture was heated to reflux for 30 min, filtered while hot and the solids were washed with ether (200 mL). The filtrate and washings were combined and concentrated to afford title compound 319 (9.62 g, 99% yield) as a beige solid. This material was used in the next step (Scheme 18) without additional purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.64 (d, J=2.0 Hz, 1H), 8.51 (dd, J=5.6, 2.0 Hz, 1H), 8.34 (s, 1H), 8.28 (dd, J=8.0, 0.8 Hz, 1H), 7.93 (dd, J=8.4, 2.0 Hz, 1H), 7.13 (t, J=9.0 Hz, 1H), 6.61 (dd, J=5.4, 0.6 Hz, 1H), 6.54 (dd, J=13.2, 2.4 Hz, 1H), 6.46 (ddd, J=8.8, 2.8, 0.6 Hz, 1H), 5.67 (s, 1H), 5.56 (s, 2H), 4.19 (dd, J=10.6, 5.0 Hz, 2H), 3.98 (td, J=12.0, 2.5 Hz, 2H), 2.09-1.99 (m, 1H), 1.49 (dt, J=13.2, 1.3 Hz, 1H). MS (m/z): 424.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])[CH3:2].[CH3:20][Mg]Br>CCOCC.[Cl-].[NH4+].[Cu](Br)Br>[Br:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]([CH3:20])[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: C[Mg]Br
Reactant: CCOC(=O)C(=Cc1ccccc1Br)C(=O)OCC
Agent: Br[Cu]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(C)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution in 500 ml of ether of 50.98 g of ethyl α-ethoxycarbonyl-o-bromo-cinnamate (170.5 mmole) and 1.0 g of copper bromide was added dropwise 56.7 ml of an ethereal solution of methylmagnesium bromide (175.6 mmole) at -20° C. The mixture was stirred overnight at room temperature, diluted with an aqueous ammonium chloride solution to separate the phases. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 3-(2-bromophenyl)-2-ethoxycarbonyl-3-methylpropionate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[O:17]=[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=2)[CH:21]=[CH:20][NH:19]1>>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][N:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[C:18]1=[O:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Product: COC(=O)c1ccc2ccn(Cc3cccc(NC(=O)OC(C)(C)C)c3)c(=O)c2c1

Procedure:
The title compound was prepared from tert-butyl[3-(bromomethyl)phenyl]carbamate (0.42 g, 1.48 mmol) and methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.20 g, 0.98 mmol) following the procedure outlined in Example 3, step 1 (0.31 g, 77%). LC-MS: (FA) ES+ 409.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([OH:33])=[O:32].C[O-].[Na+:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([O-:33])=[O:32].[Na+:36]
Reactant: O=C(NCCc1cccc(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1cccc(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
6-Chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid (40.2 mg, 0.0827 mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate (165 μL, 0.0827 mmol) at ambient temperature. After 20 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 6-chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate (42.0 mg, 0.0826 mmol, 100% yield) as a solid. MS (apci) m/z=486.0 (M+2H-Na).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[NH2:25][CH:26]1[CH:33]2[CH2:34][C:29]3([OH:36])[CH2:30][CH:31]([CH2:35][CH:27]1[CH2:28]3)[CH2:32]2>>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:21])[NH:25][CH:26]3[CH:27]4[CH2:35][CH:31]5[CH2:30][C:29]([OH:36])([CH2:34][CH:33]3[CH2:32]5)[CH2:28]4)[CH:17]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: CC(C)NC(=O)N1CCC(CCOc2cccc(C(=O)O)c2)CC1
Product: CC(C)NC(=O)N1CCC(CCOc2cccc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)c2)CC1

Procedure:
Prepared from 3-[2-(1-isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoic acid and 4-amino-1-hydroxyadamantane. 1H NMR (400 MHz, CDCl3): δ 7.31-7.37 (m, 2 H), 7.23-7.26 (m, 1 H), 7.04 (dd, 1 H), 6.37 (d, 1 H), 4.18-4.24 (m, 1 H), 4.06 (t, 2 H), 3.98 (septet, 1 H), 3.90 (d, 2 H), 2.82 (t, 2 H), 2.17-2.29 (m, 3 H), 1.92-1.99 (m, 2 H), 1.73-1.86 (m, 11 H), 1.59 (d, 2 H), 1.19-1.30 (m, 2 H), 1.16 (d, 6 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[CH3:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:35][CH2:34][C:24]2[N:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:27][C:23]=2[CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c2ccccc12)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)c2ccccc12)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol [PCT Int. Appl. (2002), WO 02/18355 A1] in tetrahydrofuran in the presence of triphenylphosphine and DIAD (diisopropyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-{4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid as colorless amorphous solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][OH:10].C(N(CC)CC)C.[Cl:18][C:19]1[S:23][C:22]([S:24](Cl)(=[O:26])=[O:25])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[S:23][C:22]([S:24]([NH:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[CH2:9][OH:10])(=[O:26])=[O:25])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: N[C@@H]1CCCC[C@H]1CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a suspension of trans-2-aminocyclohexylmethanol hydrochloride (214 mg, 1.30 mmol) and triethylamine (0.538 mL, 3.9 mmol) in 5 mL dichloromethane at 0° C. was added a solution of 5-chlorothiophene-2-sulfonyl chloride (0.267 mL, 1.23 mmol) in 1 mL dichloromethane. The reaction was stirred at 0° C. for 30 min and at room temperature for 30 min. The crude reaction mixture was purified by flash chromatography on silica gel using a gradient of 0 to 100% ethyl acetate in hexane to give 5-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (330 mg, 84%). 1H NMR (400 MHz, CDCl3) δ ppm 7.40 (d, J=4.03 Hz, 1H), 6.91 (d, J=4.03 Hz, 1H), 5.24 (d, J=7.30 Hz, 1H), 3.86 (d, J=11.33 Hz, 1H), 3.32-3.48 (m, 1H), 3.05 (d, J=6.55 Hz, 1H), 2.32 (br. s., 1H), 1.72-1.83 (m, 1H), 1.58-1.73 (m, 3H), 1.11-1.36 (m, 5H). MS [M+H]+=310; [M+Na]+=332.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a solution of DMF (50 mL) was added 1-bromo-2-nitro-4-chloro-benzene (10.0 g, 42.2 mmol), 3-hydroxybenzaldehyde (5.2 g, 42.2 mmol), and K2CO3 (11.5 g, 84.6 mmol). The solution was heated to 85° C. and stirred overnight. The reaction was poured into distill water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine, and dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound. This solid was purified by silica gel column chromatography eluting with hexanes/ethyl acetate (4:1) to give the title compound (4.4 gm, 41%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C)C=O>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:23][CH2:24]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nsc3ccccc23)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in dimethylformamide. The crude material was purified by HPLC (Zorbax XDB, reversed phase, water/acetonitrile) to yield the title compound as a white foam. MS (m/e): 460.3 (M+H+)
Reaction SMILES: N1C2C(=CC=CC=2)C([CH:11]=[C:12]2[CH:24]=[C:23]3[C:15](=[CH:16][C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]([O:25][CH3:26])=[C:13]2[O:27][CH3:28])=CC=1>CC(C)=O.C1CCCCC1>[C:12]1([CH:24]=[C:23]2[C:15]3[C:14]([O:25][CH3:26])=[C:13]([O:27][CH3:28])[CH:12]=[CH:11][C:16]=3[C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:24]=[CH:23][CH:15]=[CH:14][CH:13]=1
Reactant: COc1c(OC)c2c(cc1=Cc1ccnc3ccccc13)-c1ccccc1C=2
Solvent: C1CCCCC1
Solvent: CC(C)=O
Product: COc1ccc2c(c1OC)C(=Cc1ccccc1)c1ccccc1-2

Procedure:
9-((4-Quinolyl)methylene-1,2-dimethoxyfluorene; m.p. 210° C. (acetone/cyclohexane). Anal. Calcd. for C25H19NO2: C, 82.17; H, 5.24; N, 3.83. Found: C, 82.23; H, 5.00; N, 3.88.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([CH2:13]O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.O.[C-:20]#[N:21].[K+]>C(Cl)Cl.O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH:1]1([N:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([CH2:13][C:20]#[N:21])[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: OCc1cnn(C2CC2)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#CCc1cnn(C2CC2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A solution of (1-cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl)-methanol (Preparation 97, 1.2 g, 5.82 mmol) in DCM (15 mL) was cooled to 0° C. and thionyl chloride (0.85 mL, 11.7 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours and diluted with DCM. The organic layer was washed with water, brine and dried (Na2SO4) and evaporated in vacuo. The crude residue obtained was dissolved in dioxane (25 mL) and water (25 mL) and tetrabutyl ammonium bromide (1.38 g, 4.28 mmol) was added. The reaction mixture was stirred for 10 minutes followed by the addition of KCN (1.28 g, 19.82 mmol) and resultant mixture was stirred for a further 16 hours at room temperature. The mixture was diluted with EtOAc (50 mL) and washed with water (1×10 mL), brine (1×10 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with Hexane:EtOAc 10:90 to afford the title compound as light yellow solid (56%, 700 mg).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[N:40]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:49]3[CH2:50][CH2:51][CH:46]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH2:47][CH2:48]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: C1CC(N2CCOCC2)CCN1
Product: Cc1ccccc1-c1nc(N2CCC(N3CCOCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 87 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 4-(morpholine-4-yl)piperidine (30.7 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-[4-(morpholine-4-yl)piperidine-1-yl]-5-oxopyrimido[4,5-b][1,5]diazocine (86.5 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6]>N1C=CC=CC=1>[OH:6][CH:5]([CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[C:4]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C(=O)c2ccncc2)c1OC
Solvent: c1ccncc1
Product: COc1cccc(C(O)C2CCNCC2)c1OC

Procedure:
In Scheme F, step g, the pyridine and ketone functionality's of 4-(2,3-dimethoxybenzoyl)pyridine (12) are reduced to give 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]1[N:31]=[C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[O:29][N:28]=1>C(#N)C>[CH2:1]([C:4]1[N:5]([CH2:26][C:27]2[N:31]=[C:30]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[O:29][N:28]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: BrCc1noc(-c2cccs2)n1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccs2)n1
Yield: 64.2 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.150 g, 0.595 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (0.193 g, 0.595 mmol) and 3-(bromomethyl)-5-(2-thienyl)-1,2,4-oxadiazole (0.213 g, 0.893 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.159 g, 64% yield): MS (ES) m/z 416 (M+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:47])[C@H:18]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][N:31]2C(OC(C)(C)C)=O)=[O:29])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)[CH3:3].Cl>O1CCOCC1>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:47])[C@H:18]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][NH:31]2)=[O:29])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:15][CH2:16]1)[CH3:3]
Reactant: CN(C)Cc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)Cc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.6 %

Procedure:
To tert-butyl 3-{N-[(1R)-2-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate (Step 5) (0.31 g, 0.47 mmol) dissolved in dioxane (0.5 mL) was added 4N HCl in dioxane (1 mL). After stirring at RT for 6 h, the solvent was removed in vacuo, and the residue was purified by preparative HPLC (Waters Xterra C18 5 micron 100×20 mm, 10% to 80% CH3CN in H2O over 6.0 min, 4.63 min) to give N-[(1R)-2-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide (TFA salt) as a white solid (0.27 g). MS m/z: 560 (M+H). Calc'd for C32H38ClN5O2: 559.27. Anal. Calcd for C32H38ClN5O2-2.5 TFA-0.1 H2O: C, 52.47; H, 4.84; N, 8.27; Cl, 4.19. Found: C, 52.26; H, 4.75; N, 8.14; Cl, 4.41.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrC(Br)(Br)Br
Reactant: CCCN(c1cc(CO)cc(C(=O)OC)c1)S(C)(=O)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCN(c1cc(CBr)cc(C(=O)OC)c1)S(C)(=O)=O
Reaction time: 15 h

Procedure:
To a solution of methyl 3-(hydroxymethyl)-5-[(methylsulfonyl)(propyl)amino]benzoate (2.99 g, 9.92 mmol) in dichloromethane (90 mL) were added carbon tetrabromide (4.28 g, 12.9 mmol) and triphenylphosphine (3.12 g, 11.9 mmol). After 15 h, the reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 0-40% EtOAc/hexanes) to provide methyl 3-(bromomethyl)-5-[(methylsulfonyl)(propyl)amino]benzoate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 4.50 (s, 2H), 3.94 (s, 3H), 3.67 (t, J=7.2 Hz, 2H), 2.90 (s, 3H), 1.56-1.46 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).