Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[NH:11]C(C1CC1)=O)=[O:5])[CH3:2].N>CS(O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(=O)C2CC2)sc2ccccc12
Agent: CS(=O)(=O)O
Agent: N
Product: CCOC(=O)c1c(N)sc2ccccc12

Procedure:
The solution of 10 millimol VII in 50 milliliter methanesulfonic acid was stirred at room temperature for 48 hours. The reaction mixture was poured onto icecold 25% aqueous NH3 solution, the soliw was filtered off, washed with water and n-hexane, then dried.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:12])[NH:6][C:7]([SH:11])=[N:8][C:9]=1[CH3:10].[CH3:13][O-].[Na+].IC>CO>[OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:12])[NH:6][C:7]([S:11][CH3:13])=[N:8][C:9]=1[CH3:10]
Reactant: Cc1nc(S)[nH]c(=O)c1CCO
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nc(C)c(CCO)c(=O)[nH]1
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a stirred suspension of 90 parts of 5-(2-hydroxyethyl)-2-mercapto-6-methyl-4(3H)-pyrimidinone in 320 parts of methanol were added 90 parts of a sodium methoxide solution 30%. After stirring for 20 minutes, 72 parts of iodomethane were added and the whole was stirred and refluxed for 3 hours. The reaction mixture was evaporated in vacuo and water was added to the residue. The precipitated product was filtered off and crystallized from ethanol, yielding 78 parts (78%) of 5-(2-hydroxyethyl)-6-methyl-2-(methylthio)-4(3H)-pyrimidinone (interm. 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Mg+2].[Cl-].[Cl-].[I:13]I>C1COCC1>[I:13][C:5]1[C:4]([Cl:9])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: II
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: Clc1nc(Cl)c(I)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A dry, argon-filled Schlenk tube with a magnetic stirrer bar and septum is initially charged with 2,4,6-trichloropyrimidine (184 mg, 1 mmol) in anhydrous THF (1 ml). After adding (TMP)2Zn.MgCl2 (3.16 ml, 1.2 mmol) at 25° C., the mixture is stirred for 1 h. Then a solution of iodine (355 mg, 1.4 mmol), dissolved in anhydrous THF (2 ml), is added dropwise and the reaction mixture is stirred at 25° C. for 1 h. After dilution with aqueous sat. NH4Cl solution (30 ml) and extraction with ethyl acetate (3×30 ml), the combined organic phases are dried over Na2SO4, and distillative removal of the solvent and purification by column chromatography on silica gel (heptane:ethyl acetate) afforded the desired compound (240 mg, 78% of theory) as a colourless crystalline product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[CH3:11][O:12][C:13]1[C:18](B(O)O)=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:18]1[C:13]([O:12][CH3:11])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ncccc1B(O)O
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1cc(C=O)ccc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol), (2-methoxypyridin-3-yl)boronic acid (1.2 g, 7 mmol) and sodium hydrogen carbonate (1.5 g, 15 mmol) was stirred in dioxane (20 mL) and water (8 mL). The mixture was degassed for 10 minutes, then tetrakis(triphenylphosphine)palladium (0) (0.130 g, 0.1 mol) was added. The reaction mixture was stirred at 100° C. for 1 hour then cooled and concentrated in vacuo. The resulting residue was partitioned between EtOAc (60 mL) and water (15 mL), dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography eluting with 20% EtOAc in heptane to afford the title compound as a white solid (0.85 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(B(O)O)c(F)c1
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3F)cccc2c1N
Yield: 65.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (125 mg, 0.40 mmol) and (2-fluoro-4-methoxyphenyl)boronic acid (136 mg, 0.80 mmol) were reacted to afford the title compound (93 mg, 66% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.56 (bs, 1H), 7.88 (dd, J=8.2, 1.5 Hz, 1H), 7.69-7.77 (m, 2H), 7.43 (t, J=8.3 Hz, 1H), 6.76-6.86 (m, 2H), 3.86 (s, 3H), 3.45 (apparent q, J=6.6 Hz, 2H), 1.65 (apparent sextet, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=355 (M+H) HPLC 1.79 min.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:5]1=[O:20].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:26][C:25]=1[S:35]([NH2:38])(=[O:37])=[O:36].CO.C(OCC)C>O1CCOCC1>[CH:17]1([CH2:16][NH:15][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]([OH:14])=[C:4]([C:3]3[NH:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])=[CH:26][C:25]=4[S:35](=[O:37])(=[O:36])[N:38]=3)[C:5]2=[O:20])[CH2:18][CH2:19]1
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(NCC2CC2)C1=O
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Yield: 15.5 %

Procedure:
A solution of the product of Example 353B (0.090 g, 0.269 mmol, 1 eq.), and the product of Example 425D (0.071 g, 0.269 mmol, 1 eq.), in anhydrous dioxane (5 mL) was heated for 1 hour at 120° C. After cooling the reaction mixture to 25° C., methanol (20 mL) and diethyl ether (20 mL) were added and the precipitated product collected by vacuum filtration to give the title compound (21 mg, 15.5% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.16 (m, 2 H) 0.41 (m, 2 H) 1.07 (m, 1 H) 2.85 (m, 2 H) 3.10 (s, 3 H) 6.44 (m, 1 H) 7.44 (t, J=7.54 Hz, 1 H) 7.62 (m, 2 H) 7.71 (m, 1 H) 7.90 (t, J=7.91 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.17 (d, J=6.99 Hz, 1 H) 10.30 (m, 1 H) 14.15 (m, 1 H). MS (ESI+) m/z=504 (M+H)+.
Reaction SMILES: C(O)(=O)C.[C:5]1([C:11]2[CH:20]=[C:19]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.[Pt]=O>[C:5]1([C:11]2[CH:20]=[C:19]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(-c2cc(CCc3ccccn3)c3ccccc3n2)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(-c2cc(CCC3CCCCN3)c3ccccc3n2)cc1

Procedure:
4.55 ml of concentrated acetic acid are added to a solution containing 2.5 g of 2-phenyl-4-[2-(2-pyridyl)-ethyl]-quinoline in 250 ml of ethanol, then 0.5 g of 82% platinum oxide is added as catalyst. Hydrogenation is effected at 30° C., under a hydrogen pressure equal to the normal pressure for 6 hours, at the end of which time 700 ml of hydrogen have been absorbed. The catalyst is eliminated by filtration. The ethanol is evaporated under reduced pressure and the residue is taken up with 200 ml of water. The aqueous phase is made alkaline by means of concentrated ammonia, and extracted with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is fixed on a column of 200 g of silica and eluted with a 9/1 toluene-diethylamine mixture. 0.65 g are thus isolated of 2-phenyl-4-[2-(2-piperidyl)-ethyl]-quinoline in the form of an oil. This compound is dissolved in acetone and converted, by addition of hydrochloric acid, to its dihydrochloride, which melts at 200° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COC(=O)c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc2c(c1)CCN2Cc1cccc([N+](=O)[O-])c1

Procedure:
A mixture of the indoline (Example 31) (4.39 g), 3-nitrobenzyl bromide (5.02 g) and anhydrous potassium carbonate (3.17 g) in methylethylketone (150 ml) was heated under reflux for 18 hours. On cooling, the inorganics were filtered off and the solvent removed in vacuo. The reaction mixture was extracted from water into ethyl acetate, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with chloroform, gave methyl 1-(3-nitrobenzyl)indoline-5-carboxylate, m.p. 99°-100° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[O:9][C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=1[F:25]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1nn(C)c(Br)c1Oc1ccc(F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(C)c(-c2ccc(F)cc2F)c1Oc1ccc(F)cc1Cl
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-4-(2-chloro-4-fluorophenoxy)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step C) (250 mg, 0.78 mmol) in 1,2-dimethoxyethane/water (5 mL, 2:1) was sparged with a subsurface stream of argon for 30 minutes, and then 2,4-difluorophenylboronic acid (371 mg, 2.34 mmol), potassium carbonate (1.08g, 7.82 mmol) and tetrakis(triphenylphosphine)palladium (90 mg, 0.078 mmol) were added. The reaction mixture was heated to 80° C. for 15 h, and then cooled and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (5 to 30% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a pale yellow solid (150 mg) melting at 70-72° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][CH2:10][CH2:11][C@@H:12]2[CH2:14][C@@H:13]2[CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]3([CH3:27])[CH2:26][CH2:25]3)=[O:22])[CH2:17][CH2:16]2)=[CH:7][CH:6]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:27][C:24]1([O:23][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C@H:13]3[CH2:14][C@H:12]3[CH2:11][CH2:10][O:9][C:8]3[CH:28]=[CH:29][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:6][CH:7]=3)[CH2:16][CH2:17]2)=[O:22])[CH2:25][CH2:26]1
Reactant: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methylcyclopropyl 4-((1R,2S)-2-{2-[4-(2-methoxy-2-oxoethyl)phenoxy]ethyl}cyclopropyl)piperidine-1-carboxylate (Example 53, Step A, 88 mg, 0.21 mmol) in a 1:1:1 mixture of THF/methanol/water (3 mL) was added lithium hydroxide (10.7 mg, 0.44 mmol) and the resulting mixture stirred for 2 h at RT. The mixture was neutralized via addition of 1N aqueous HCl until pH of 7 was obtained. The solution was then extracted with ethyl acetate (3×10 mL). The organics were combined, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford the title compound used for the next reaction without further purification. HPLC/MS; 1.22 min, 401 (M+H)+.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.O.[OH-].[Li+].C(OCC)(=O)C>CS(C)=O>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4]2([O:17][CH:2]([CH2:18][OH:1])[CH2:3]2)[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC2CO2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(CO)O2
Temperature: 140 °C
Yield: 23.7 %

Procedure:
To a solution of 1.42 g of 4-(2,3-epoxypropan-1-yl)-1-(tert-butoxycarbonyl)piperidin-4-ol in dimethyl sulfoxide (20 ml) were added in a nitrogen atmosphere 5 ml of water and 2.32 g of lithium hydroxide and the resulting mixture was heated to 140° C. for 30 minutes. After adding ethyl acetate, the reaction mixture was washed with water thrice. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichloromethane/ethyl acetate) to thereby give 0.336 g of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.[CH:36](N(CC)C(C)C)([CH3:38])[CH3:37].C(I)(C)C>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([CH:36]([CH3:38])[CH3:37])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(C(C)C)C3)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of compound xc: (S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.097 g, 0.24 mmol) in dry N,N-Dimethylformamide (1.30 mL, 16.8 mmol) was added N,N-Diisopropylethylamine (0.1270 mL, 0.7291 mmol) followed by Isopropyl iodide (0.0488 mL, 0.488 mmol). The reaction mixture was heated at 50° C. and stirred overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.15 (d, J=8.7, 2H), 7.46 (d, J=8.7, 2H), 6.16 (t, J=5.5, 1H), 3.97 (s, 1H), 3.85 (d, J=10.7, 1H), 3.77 (d, J=11.4, 1H), 3.68 (t, J=13.3, 3H), 3.60-3.49 (m, 2H), 3.40 (t, J=11.0, 1H), 3.18-3.04 (m, 2H), 2.91-2.64 (m, 3H), 2.57 (d, J=15.4, 1H), 1.89-1.63 (m, 2H), 1.06 (t, J=7.5, 9H), 0.94 (t, J=6.3, 1H), 0.82 (t, J=7.4, 3H). LC/MS-m/z+453.2 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:20])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[C:12]([O:18][CH3:19])[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]Cl)[CH2:23][CH2:22]1>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([O:17][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8](=[O:20])[O:9]2)=[CH:14][CH:13]=1
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(=O)oc2c1
Reactant: ClCCN1CCOCC1
Product: COc1ccc2c(OCCN3CCOCC3)c(-c3ccccc3)c(=O)oc2c1
Yield: 70.8 %

Procedure:
This compound is prepared according to the method described in Example 8 from 24.2 g. (0.09 mol) of 3-phenyl-4-hydroxy-7-methoxy-coumarin and 17.5 g. (0.117 mol) of 2-morpholino-1-chlorethane. After recrystallisation from a mixture of diisopropyl ether and ethyl acetate (70-30), 24.3 g. of a white solid are obtained. M.P. 95°-96° C.; yield 70.8% (theoretical yield 34.3 g.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]#[C:14][Si](CC)(CC)CC)[C:5]([O:7][CH2:8][CH3:9])=[O:6].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:13]([C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[CH3:1])#[CH:14]
Reactant: CCOC(=O)c1ccc(C#C[Si](CC)(CC)CC)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)OCC)cc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 3-methyl-4-((triethylsilyl)ethynyl)benzoate (from the previous step) (1.0 eq.) in THF (0.3 M) at 0° C. was added dropwise 1.0 M TBAF in THF (1.2 eq.). After stirring for 10 minutes at 0° C., the reaction was quenched with saturated aqueous sodium bicarbonate solution. The two phases were separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% ethyl acetate in hexane to give ethyl 4-ethynyl-3-methylbenzoate as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].[Cl:8]/[C:9](=[CH:14]\N(C)C)/[CH:10]=[N+](C)C.CCN1C2C(S/C/1=C\C#C/C(/C)=C\C1SC3C(=CC=CC=3)[N+]=1CC)=CC=CC=2.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(#N)C.O>[Cl:8][C:9]1[CH:10]=[N:4][C:3]([C:2]([F:7])([F:6])[F:1])=[N:5][CH:14]=1
Reactant: N=C(N)C(F)(F)F
Reactant: CN(C)/C=C(\Cl)C=[N+](C)C
Agent: CCN1/C(=C/C#C/C(C)=C\c2sc3ccccc3[n+]2CC)Sc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: FC(F)(F)c1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
A solution of 4.70 g (85% purity, 35.65 mmol) of trifluoroacetamidine and 10.93 g (35.65 mmol) of ((Z)-2-chloro-3-dimethylamino-allylidene)-dimethyl-ammonium; hexafluoro phosphate [Davies, Ian W.; Marcoux, Jean-Francois; Wu, Jimmy; Palucki, Michael; Corley, Edward G.; Robbins, Michael A.; Tsou, Nancy, Ball, Richard G.; Dormer, Peter; Larsen, Robert D.; Reider, Paul J, Journal of Organic Chemistry 2000, 65(15), 4571-4574] in 70 ml acetonitrile was treated with 4.33 ml (42.78 mol) of triethylamine and stirred for 4 h at room temperature. The reaction was poured into 250 ml of water and extracted with ether (three times). The organic phases were washed with water (two times), dried (Na2SO4) and carefully evaporated to give 3.66 g of the title compound as an orange volatile liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@@H:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:15]([C:24]([O:26]C)=[O:25])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+].O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@@H:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:15]([C:24]([OH:26])=[O:25])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)C2(c3ccc(Cl)cc3)CC2)C[C@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CN(C(=O)C2(c3ccc(Cl)cc3)CC2)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (3S,4R)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidine-3-carboxylate (50 mg, 0.0001 mol, example 39) in tetrahydrofuran (2 mL, 0.02 mol) was added lithium hydroxide (9.4 mg, 0.00039 mol) and water (0.5 mL, 0.03 mol) and the solution was stirred at rt for 1 h. The reaction mixture was then acidified (pH ˜2) and was extracted with AcOEt. The organic layer was dried (over MgSO4), and concentrated to afford the product. LCMS: m/z 370.4 (M+H)+
Reaction SMILES: [N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:7])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:55][C@@H:56]1[C:62](=[O:63])[N:61]([CH2:64][C:65]2[C:74]3[C:69](=[CH:70][C:71]([Br:75])=[CH:72][CH:73]=3)[CH:68]=[CH:67][C:66]=2[O:76][CH3:77])[C:60]2[CH:78]=[CH:79][CH:80]=[CH:81][C:59]=2[NH:58][CH2:57]1>CN(C=O)C>[C:11]([O:10][C:8](=[O:9])[N:1]([C@H:2]([C:4](=[O:6])[NH:55][C@@H:56]1[C:62](=[O:63])[N:61]([CH2:64][C:65]2[C:74]3[C:69](=[CH:70][C:71]([Br:75])=[CH:72][CH:73]=3)[CH:68]=[CH:67][C:66]=2[O:76][CH3:77])[C:60]2[CH:78]=[CH:79][CH:80]=[CH:81][C:59]=2[NH:58][CH2:57]1)[CH3:3])[CH3:7])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)CNc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Yield: 90.2 %

Procedure:
Boc-N-Me-Ala-OH (650 mg, 3.19 mmol), HATU (1.32 g, 3.48 mmol) and DIPEA (1.52 mL, 8.72 mmol) were added to a solution of (S)-3-amino-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one trifluoroacetate (1.6 g, 2.90 mmol) in DMF (10 mL). After 18 the mixture was evaporated and the mixture diluted with ethyl acetate. The mixture was washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography to afford the title compound (1.6 g, 88%) as a yellow solid. LC-MS: 611 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:35](C(C2C=NC(Cl)=CC=2)=O)[S:36]([CH3:39])(=[O:38])=[O:37])[C:8]([O:33][CH3:34])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28](Cl)=[N:27][CH:26]=4)=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>COC[C@@H](N)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[C:8]([O:33][CH3:34])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([NH:35][C@@H:7]([CH3:6])[CH2:8][O:33][CH3:34])=[N:27][CH:26]=4)=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(NC(=O)c2cc3cccc(NC(=O)c4ccc(Cl)nc4)c3s2)cc(C(C)(C)C)cc1N(C(=O)c1ccc(Cl)nc1)S(C)(=O)=O
Agent: COC[C@H](C)N
Product: COC[C@H](C)Nc1ccc(C(=O)Nc2cccc3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)sc23)cn1
Temperature: 100 °C
Yield: 110.1 %

Procedure:
To N-(2-{5-tert-butyl-3-[(6-chloro-pyridine-3-carbonyl)-methanesulfonyl-amino]-2-methoxy-phenylcarbamoyl}-benzo[b]thiophen-7-yl)-6-chloro-nicotinamide (see Example 1) (33 mg) in a sealed tube was added (S)-(+)-1-methoxy-2-propylamine (150 μL). The reaction was purged with Ar and then heated to 100° C. in the sealed tube 12 h. The reaction mixture was cooled to room temperature and diluted with EtOAc, washed with NH4Cl solution, water, and brine. The organics were dried over MgSO4, filtered and concentrated down to give the crude product which was purified by flash chromatography on silica gel (CH2Cl2-2% MeOH/CH2Cl2) to give the title compound (16 mg, 53%) as a yellow foam.