Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13].Br[CH2:15][C:16](=O)[CH2:17][CH3:18].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:17]([C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([CH2:11][CH2:12][CH3:13])[CH:4]=2)[O:7][CH:15]=1)[CH3:18]
Reactant: CCC(=O)CBr
Reactant: CCCc1cc(C(N)=O)ccc1O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCc1cc(-c2nc(CC)co2)ccc1O
Yield: 48.8 %

Procedure:
A mixture of 4-hydroxy-3-propylbenzamide (200.0 mg, 1.1 mmol) (Example 43), 1-bromo-2-butanone (0.19 mL, 1.7 mmol), toluene (1.5 mL), and 1,4-dioxane (1.5 mL) was heated at reflux for 8 h with a Dean-Stark trap. The solvents were evaporated. The crude product was purified on HPLC to yield a solid (124.2 mg, 48%). LC/MS m/z 232 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.56-7.76 (m, 3H), 6.85 (d, J=8.4 Hz, 1H), 2.46-2.56 (m, 4H), 1.52-1.61 (m, 2H), 1.18 (t, J=7.6 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in a analogous manner to Example 61e. Product isolated as an off-white solid (0.013 g, 13%). MP: 170-175° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 10.95 (br s, 1H), 8.64 (d, 1H, J=8.3 Hz), 8.12-8.06 (m, 2H), 7.54-7.39 (m, 3H), 7.08 (t, 1H, J=7.6 Hz), 6.64 (s, 1H), 6.22-6.12 (m, 1H), 6.07-5.74 (m, 1H), 3.86 (s, 3H), 3.52 (p, 2H, J=6.8 Hz), 2.99-2.71 (m, 13H). MS: 531 (MH)+.
Reaction SMILES: C1(C[O:5][C:6]2[C:7]3[C:11]([CH:12]=[CH:13][CH:14]=2)=[N:10][N:9]([CH3:15])[C:8]=3[S:16]([NH2:19])(=[O:18])=[O:17])CC1.Cl>C(O)(=O)C>[OH:5][C:6]1[C:7]2[C:11]([CH:12]=[CH:13][CH:14]=1)=[N:10][N:9]([CH3:15])[C:8]=2[S:16]([NH2:19])(=[O:18])=[O:17]
Reactant: Cn1nc2cccc(OCC3CC3)c2c1S(N)(=O)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cn1nc2cccc(O)c2c1S(N)(=O)=O
Yield: 69.9 %

Procedure:
A mixture comprising 62 g (221 mmol) of 4-cyclopropylmethoxy-2-methyl-2H-indazole-3-sulfonamide, 120 ml of acetic acid and 120 ml of concentrated hydrochloric acid, was stirred at 80° C. for one hour. After concentrating acetic acid-hydrochloric acid, the mixture was poured into ice water. Crystals were collected by filtration and washed with water. Further, the crystals were washed with IPE and dried to obtain 35.1 g (yield: 70%) of the desired product. Melting point: 180°-181° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][O:14][CH2:15][CH2:16][OH:17]>C(OCC)C.Cl>[CH3:1][O:2]/[N:3]=[C:4](\[C:5]1[O:17][CH2:16][CH2:15][O:14][N:13]=1)/[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6]
Reactant: CON=C1C(=NOCCO)Oc2ccccc21
Agent: Cl
Solvent: CCOCC
Product: CO/N=C(\C1=NOCCO1)c1ccccc1O
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
2 g of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-(O-methyl-oxime) (II-1) (content according to HPLC analysis 96.88%, 0.0082 mol) prepared by the method of process e) are dissolved in 50 ml of diethyl ether saturated beforehand with hydrogen chloride gas at 0° C. Without further cooling, the mixture is stirred for 30 minutes, the solvent is then distilled off under reduced pressure and the residue is taken up once more in diethyl ether. Some of the product crystallizes out and is filtered off. The mother liquor is concentrated under reduced pressure and the residue is dissolved in 25 ml of diethyl ether saturated with hydrogen chloride gas at 0° C. Without further cooling, the solution is stirred for a further 30 minutes, the solvent is distilled off under reduced pressure and the residue is once more taken up in diethyl ether. A further fraction of the product crystallizes out and is likewise filtered off. In total, 1.37 g (69% of theory) of (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) are obtained (content according to HPLC analysis: 97.59%).
Reaction SMILES: [CH:1]1([C@@H:4]([NH2:6])[CH3:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:18]3[N:19]=[C:20]4[C:26]([C:27](O)=[O:28])=[CH:25][N:24]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]4=[N:22][CH:23]=3)=[N:13][N:14]2[CH3:17])=[CH:10][CH:9]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C@@H:4]([NH:6][C:27]([C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([C:12]4[C:11]5[C:15](=[CH:16][C:8]([Cl:7])=[CH:9][CH:10]=5)[N:14]([CH3:17])[N:13]=4)[N:19]=3)[N:24]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=2)=[O:28])[CH3:5])[CH2:3][CH2:2]1
Reactant: C[C@H](N)C1CC1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CC1

Procedure:
A solution of (S)-1-cyclopropylethanamine (32 mg, 0.373 mmol), 3 mL of dichloromethane, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (77 mg, 0.169 mmol), 4-dimethylaminopyridine (21 mg, 0.169 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (71 mg, 0.371 mmol) was stirred 18 h, then concentrated to an off-white solid. The solid was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution. The organic layer was sequentially washed with 10 mL of water, 10 mL of a 10% NaOH solution, 10 mL of water, and 10 mL of a sat. aq. NaCl solution; dried over Na2SO4, filtered and concentrated to 70 mg (80%) of crude 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide, which was used without further purification. MS: (M+Na)+=547.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18](=[O:36])[CH:19](Br)[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:36])[CH:19]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:27])=[O:28])=[CH:22][CH:21]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)C(Br)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A mixture of 2, 4 difluorophenol (0.28 g, 2.18 mmol) and cesium carbonate (0.39 g, 1.19 mmol) in acetonitrilie (20 ml) stirred for 30 mins. A solution of bromo-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.75 g, 1.98 mmol) in acetonitrile (5 ml) was added drop wise at room temperature and stirred further for 2 hrs. Reaction mixture was diluted with ethyl acetate (50 ml), washed with water, 1N NaOH (cold, 50 ml), and brine (50 ml) dried over anhydrous sodium sulfate, filtered and concentrated to provide (2,4-difluoro-phenoxy)-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.35 gm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:28]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:20]>CC(C)=O.CN(C=O)C>[CH2:19]([O:21][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:12][C:4]2[CH:5]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:7]=[C:2]([Br:1])[CH:3]=2)[C:28]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:20]
Reactant: CS(=O)(=O)c1cc(O)cc(Br)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
To a solution of 3-bromo-5-methanesulfonyl-phenol (1.3 g) in a mixture of acetone and DMF (2:1, 60 mL) were added potassium carbonate (7.1 g) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.7 g). The resulting mixture was stirred at 75° C. for 1 day. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (2.9 g, 87% yield). LRMS calcd for C30H41O8BrS [M+H]+ 641.2, observed 641.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2cccc(C(=O)O)n2)c1
Yield: 95 %

Procedure:
Method 1 was followed using 6-bromopicolinic acid (1.0 equiv.) and 2-fluoro-5-methoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-(2-fluoro-5-methoxyphenyl)picolinic acid in 95% yield. LC/MS=248.2 (M+H), Rt=0.78 min.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([CH2:16][O:17][CH3:18])[CH:15]=1)[C:11]#[N:12])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([CH2:16][O:17][CH3:18])[CH:15]=1)[C:11]#[N:12]
Reactant: COCc1cc(C#N)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCc1cc(C#N)cc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 3-(tert-butyl-dimethyl-silanyloxymethyl)-5-methoxymethyl-benzonitrile (1.402 g, 4.810 mmol) in tetrahydrofuran (10 mL) at room temperature was added tetrabutylammonium fluoride (5.051 mL, 5.051 mmol, 1 M in tetrahydrofuran). The reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40% ethyl acetate in hexanes yielded 3-hydroxymethyl-5-methoxymethyl-benzonitrile (713 mg, 84%).
Reaction SMILES: [F:1][C:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3]>CCO.O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:2]([F:1])([F:4])[CH3:3])[CH2:6][CH2:7]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(F)(F)[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Solvent: CCO
Solvent: O
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
(R)-4-(6-(cis-4-(1,1-Difluoroethyl)cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (32 mg, 0.083 mmol) was dissolved in EtOH (5 mL). Then LION (60 mg, 2.5 mmol, 30.0 eq.) in 1 mL water was added to the mixture. The mixture was heated to 80° C. and stirred for 15 h. LCMS showed starting material was gone. Solvent was removed. DCM was added and filtered. The filtrate was concentrated and purified by silica gel chromatography using DCM/methanol (10/1) to give product (12 mg, 40%) as a slight yellow solid. EDI-MS (M-NH2): 347.0. HPLC: 98.82%. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.72-7.66 (m, 2H), 7.49 (d, 1H), 7.10 (d, 2H), 4.30-4.27 (m, 1H), 3.78-3.68 (AB, 2H), 3.18 (b, 3H), 2.32-2.30 (m, 2H), 2.04-1.99 (m, 2H), 1.63-1.19 (m, 11H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]([N:14]2[CH2:13][C@@H:12]([N:10]([C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:24])[CH3:11])[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15]2)=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound 4-{(3R,4S)-3-(4-chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using piperidine-1,4-dicarboxylic acid mono-tert-butyl ester instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a light-brown gum. MS m/e: 560.3 [M]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:35]([O:37][C:38]([C:40]([NH2:43])([CH3:42])[CH3:41])=[O:39])[CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH:43][C:40]([C:38]([O:37][CH2:35][CH3:36])=[O:39])([CH3:42])[CH3:41])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)N
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)NC(=O)c1ccc(S(=O)(=O)n2c(=O)n(C3CCCCC3)c3cc(OCC)ccc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
500 mg of the compound obtained in Example 13, 300 mg of 1-ethoxycarbonyl-1-methylethylamine hydrochloride and 550 mg of BOP were mixed with 2 ml of DIPEA and 50 ml of DCM and the reaction medium was stirred for 30 minutes at room temperature. It was then concentrated under vacuum and the residue was taken up with water and then extracted with AcOEt, washed successively with 1N HCl , with 1N NaOH and then with water, dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography on a silica column using a DCM/AcOEt mixture (97/3; v/v) as the eluent. 170 mg of the expected product were obtained in the form of a white solid by crystallization from an AcOEt/iso ether mixture (10/90; v/v). M.p.=202° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Cl.O1CCOCC1>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:23])([F:24])[F:25])[NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C(F)(F)F)n2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2)c1
Yield: 93 %

Procedure:
A solution of 4-Methyl-2-[4′-trifluoromethyl-5-(6-trifluoromethyl-pyridin-2-yl)-biphenyl-3-yl]-pentanoic acid ethyl ester, compound 7a (865 mg, 1.7mmol) in MeOH (50 mL), platinum oxide (39.0 mg, 0. 17 mmol) and 4N HCl/dioxane (500 μl) was hydrogenated at 20 psi for 4 hours. The reaction mixture was filtered through celite, washed with MeOH and concentrated in vacuo. The residue was partitioned between dichloromethane and Na2CO3 to give the free base. Purification by silica gel chromatography gave the desired product (813 mg, 93%) (M+H) 515.53, Found 516.3.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[ClH:10].[Cl:11]N1C(=O)CCC1=O>C(OCC)C.C(O)(=O)C>[ClH:11].[Cl:10][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1cccnc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(CCl)c1cccnc1

Procedure:
To a solution of 100 g (0.83 moles) of 3-acetylpyridine in diethyl ether (1 L) was added of 1 M hydrogen chloride in ether (950 mL) with rapid stirring. The precipitated solids were filtered, washed with ether and dried. The hydrochloride salt (129 g, 0.83 moles) was added to a 5 L reactor equipped with a mechanical stirrer and dissolved with 1 M hydrogen chloride in acetic acid (830 mL). The mixture was stirred until a clear solution was obtained. N-chlorosuccinimide (111 g, 0.83 moles) was added, and a yellow mixture resulted. The solution was stirred at room temperature for 18 hours, gradually becoming a colorless suspension. The solids were collected by filtration and washed with ether. The filtrate was treated overnight with 80 g of N-chlorosuccinimide and additional product was collected to give a combined yield of 152 g. 1H NMR (DMSO-d6) δ 10.3 (br s, 1 H), 9.27 (s, 1 H), 8.96 (d, J=5.1 Hz, 1 H), 8.62 (d, J=9.9 Hz, 1 H), 7.89 (m, 1 H), 5.30 (s, 2 H); MS (EI) m/z 155 (M+).
Reaction SMILES: O.Cl.ICC([O:7][C:8]1[C:13]2[C:14](=[O:31])[C:15]3[C:27]([C:28](=[O:29])[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[C:26]1[N:17]([CH2:18][C:19]2[C:24]([CH:25]1[CH3:30])=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=3)=O>O1CCCC1>[OH:7][C:8]1[C:13]2[C:14](=[O:31])[C:15]3[C:27]([C:28](=[O:29])[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[C:26]1[N:17]([CH2:18][C:19]2[C:24]([CH:25]1[CH3:30])=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=3
Reactant: CC1c2ccccc2Cn2cc3c(c21)C(=O)c1cccc(OC(=O)CI)c1C3=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1c2ccccc2Cn2cc3c(c21)C(=O)c1cccc(O)c1C3=O
Yield: 92.1 %

Procedure:
Water (312 ml) and concentrated hydrochloric acid (169 ml) were added to a suspension of 5,8,13,14-tetrahydro-9-[iodoacetoxy]-14-methylbenz[5,6]isoindolo[2,1-b]isoquinolin-8,13-dione (80.0 g, Intermediate 9 in GB-A-2175587) in tetrahydrofuran (1.335 L). This mixture was stirred and heated to reflux under nitrogen for 18 h and part (550 ml) of the solvent was removed by distillation at atmospheric pressure. The resulting suspension was stirred and cooled to ca. 5° for 4.5 h, and the solid was collected by filtration, washed with cold tetrahydrofuran and dried in vacuo to give the title compound (48.8 g); λmax 243 nm (MeOH), E11 1022; δ(CDCl3) 12.98 (OH, s, 1H), 5.27 (5-H, d, 16 Hz, 1H), 5.16 (5-H, d, 16 Hz, 1H), 4.98 (14-H, q, 7 Hz, 1H), 1.55 (14-CH3, d, 7 Hz, 3H).
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][CH:14]([S:17][C:18]1[CH:23]=[CH:22]C(O)=[CH:20][CH:19]=1)[CH2:15][CH3:16].O>CN(C=O)C>[CH3:13][CH:14]([S:17][C:18]1[CH:23]=[CH:22][C:1]([O:2][CH2:3][CH2:4][OH:5])=[CH:20][CH:19]=1)[CH2:15][CH3:16]
Reactant: CCC(C)Sc1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Sc1ccc(OCCO)cc1

Procedure:
A mixture of ethylene carbonate (41.08 g, 460.0 mmol) and potassium carbonate (63.57 g, 460.0 mmol) in 100 ml of DMF is heated to 110° and 4-(1-methylpropylthio)phenol (40.19 g, 230.0 mmol) in 100 ml DMF is slowly added dropwise with stirring. The mixture is stirred at 100° for 8 hours. Water is added to the cooled reaction mixture and the aqueous phase is extracted with ether. The combined organic layers are washed with 5% NaOH, with water and with brine, dried and the solvent removed to give 2-[4-(1-methylpropylthio)phenoxy]ethanol.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:19][CH2:18]1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])CC1

Procedure:
To a solution of ethyl 4-fluoro-3-nitrobenzoate (2.13 g) and 1-methylpiperidin-4-amine (1.14 g) in tetrahydrofuran (40 mL) was added N,N-diisopropylethylamine (5 mL). The mixture was then stirred at reflux overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (300 mL) and washed with aqueous NaHCO3, water and brine. After evaporation of the solvent, the residue was dissolved in tetrahydrofuran (20 mL), methanol (10 mL) and water (10 mL). Then, LiOH H2O (2 g) was added. The mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was neutralized with 5% aqueous HCl. The precipitate was filtered, washed with brine, and dried under vacuum to give the product.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:23](#N)C.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][N:18]([CH3:23])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC#N
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCCC(C)(C)c1ccc(C2=CCCN(C)C2)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 25° C. solution of 1.0 g. (3.32 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine in 15 ml. of acetonitrile is added 1.32 ml. (17.6 mmoles) of 37% formaldehyde solution. After stirring for one hour the reaction is cooled to 0° C. and 332 mg. (5.3 mmole) of sodium cyanoborohydride added. The reaction mixture is allowed to warm to 25° C. over a one hour period while the pH is maintained at 7 by the addition of acetic acid. The reaction mixture is evaporated, made basic with 2 N potassium hydroxide and extracted with 200 ml. of dichloromethane. The organic extract is dried over magnesium sulfate and evaporated. The residue is crystallized from ether-pentane to yield 350 mg. of the title compound.