Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[S:13][C:14]=2[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH2:9])=[N:6][CH:7]=1>C(O)C.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[S:13][C:14]=2[CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[CH3:9])=[N:6][CH:7]=1
Reactant: C=C(c1ccc(F)cn1)c1c(CCN(C)C)sc2ccccc12
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(c1ccc(F)cn1)c1c(CCN(C)C)sc2ccccc12
Reaction time: 3 h

Procedure:
To a solution of (2-{3-[1-(5-fluoro-pyridin-2-yl)-vinyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (133 mg, 0.407 mmol) in ethanol (7 mL), platinum dioxide (50 mg, 0.2 mmol) was added. Reaction was shaken at 35 psi for 3 hours and at 40 psi for 3 hours under an atmosphere of hydrogen. The reaction mixture was filtered and washed with EtOH. Purification by mass triggered preparative HPLC afforded (2-{3-[1-(5-fluoro-pyridin-2-yl)-ethyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (Compound 7-3). (MH+=329, tR=40.592, Method 2) The enantiomers (2-{3-[(R)-1-(5-fluoro-pyridin-2-yl)-ethyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (Compound 7-4) (MH+=329.0, tR=4.617, Method 2) and (2-{3-[(S)-1-(5-fluoro-pyridin-2-yl)-ethyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (Compound 7-5) (MH+=329.0, tR=4.554, Method 2) were separated using a chiral HPLC OJ-H column, Eluent: Hexanes:EtOH=90:10 with 0.1% DEA.
Reaction SMILES: [N+:1]1([O-:10])[O:5][N:4]=[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=12.[C:11]([CH2:19][C:20](=O)[CH3:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C>[C:11]([C:19]1[C:20]([CH3:21])=[N+:4]([O-:5])[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N+:1]=1[O-:10])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: [O-][n+]1onc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred suspension of 80 g. (0.59 mol.) of benzofurazan 1-oxide and 95 g. (0.59 mol.) of benzoylacetone in 1,000 ml. of ethanol was added 1.6 g. (0.04 mol.) of finely divided sodium hydroxide. The mixture became clear after about 30 minutes. Stirring was continued for a further 16 hours, and then the solid which had precipitated was collected by filtration. It was washed with ethanol, and dried to afford 153 g. (92% yield) of 2-benzoyl-3-methylquinoxaline 1,4-dioxide, m.p. 229°-231° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:19]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>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.C(=O)([O-])[O-].[Na+].[Na+]>[C:7]([C:6]1[CH:9]=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=2)[CH:3]=[CH:4][C:5]=1[O:10][C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])#[N:8]
Reactant: CCCCCC[C@@H](C)Oc1ccc(Br)cc1C#N
Reactant: CCCCCCCCCCOc1ccc(B(O)O)cc1
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+]
Product: CCCCCCCCCCOc1ccc(-c2ccc(O[C@H](C)CCCCCC)c(C#N)c2)cc1

Procedure:
Quantities: compound 42 (1.50 g, 4.84 mmol), compound 87 (1.61 g, 5.81 mmol), aqueous sodium carbonate (2 M, 20 ml), tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol),
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C@H:2]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[C:3]([NH2:5])=[O:4])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: NC(=O)[C@H](N)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: NC(=O)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)c1ccc(F)cc1

Procedure:
The title compound was synthesized according to the procedure of Preparation 3 employing (R)-2-amino-2-(4-fluoro-phenyl)-acetamide and 4-chlorobenzenesulfonylchloride to afford the desired product. 1HNMR (400 MHz, CD3OD)δ 4.87 (s, 1H), 6.94 (m, 2H), 7.24 m, 2H), 7.6 (dd, 4H, J=2.1, 103).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:25][CH:24]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)OCC(OCC)=O>>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:34][CH:35]=1
Reactant: CCOC(=O)COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: CCOC(=O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(O)COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 15 and making non-critical variations using ethyl {4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetate to replace ethyl {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetate, {4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetic acid was obtained (88%) as a colorless solid: mp 265-266° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.99 (s, 1H), 7.33-7.21 (m, 3H), 7.19-7.14 (m, 1H), 7.05-6.98 (m, 2H), 6.93-6.86 (m, 2H), 6.43 (s, 1H), 6.41 (s, 1H), 4.86 (q, J=15.5 Hz, 2H), 4.79 (ABq, J=38.0, 9.3 Hz, 2H), 4.65 (s, 2H), 4.55-4.46 (m, 2H), 3.04-2.90 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 170.1, 161.1, 160.6, 157.0, 142.1, 132.1, 128.7, 128.5, 123.6, 122.9, 120.4, 119.8, 118.8, 114.6, 109.4, 92.4, 79.8, 72.0, 64.3, 56.9, 42.4, 28.3; MS (ES+) m/z 443.8 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=O)[C:7]=2[N:8]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:9]1[C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=[CH:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc2cc[nH]c(=O)c2n1
Product: CSc1ncc2ccnc(Cl)c2n1
Yield: 86 %

Procedure:
A solution of 2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (Preparation 32, 1.47 g, 7.61 mmol) in POCl3 (70 mL) was heated to 70° C. for 18 hours. The reaction was concentrated under reduced pressure and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 20% EtOAc in cyclohexane to give the title compound (1.39 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:13]([CH3:14])=[CH:12][NH:11][C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1.[H-].[Na+].[F:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1>COCCOC>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][N:11]3[C:5]4[N:6]=[C:7]([S:9][CH3:10])[N:8]=[C:3]([O:2][CH3:1])[C:4]=4[C:13]([CH3:14])=[CH:12]3)=[CH:26][CH:25]=2)=[O:23])=[CH:32][CH:33]=1
Reactant: COc1nc(SC)nc2[nH]cc(C)c12
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1nc(SC)nc2c1c(C)cn2Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Yield: 84 %

Procedure:
Under argon gas, 4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (4.18 g) was dissolved in anhydrous DME (120 ml). Then, with ice-cooling and stirring, 60% sodium hydride-oil (0.88 g) was added in 3 installments. After completion of addition, the mixture was stirred for 30 minutes, at the end of which time a solution of 4-(4-fluorobenzoyl)benzyl bromide (6.74 g) in anhydrous DME (20 ml) was added. Then, at room temperature, the mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, whereupon colorless needles separated out. These crystals were collected by filtration, rinsed with ethyl acetate, and dried to provide the title compound (7.07 g). 1H-NMR (CDCl3) 5: 2.33(3H,d,J=1.2Hz), 2.61(3H,s), 4.09(3H,s), 5.37(2H,s), 6.58(1H,d,J=1.2Hz), 7.15(2H,t,J=8.6Hz), 7.29(2H,d,J=8.4Hz), 7.71(2H,d,J=8.4Hz), 7.82(2H,dd,J=5.4&8.8Hz).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[O:14]=[S:15]1(=[O:43])[C:21]2[CH:22]=[C:23]([OH:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=2[N:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:18][C:17]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:16]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[O:43]=[S:15]1(=[O:14])[C:21]2[CH:22]=[C:23]([O:28][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:24]([O:26][CH3:27])=[CH:25][C:20]=2[N:19]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:18][C:17]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:16]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(OC)c(O)cc2S(=O)(=O)C1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(OC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Yield: 99 %

Procedure:
Ethyl bromoacetate (0.13 ml), Na2CO3 (0.40 g) and tetrabutylammonium bromide (0.030 g) were added to a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (synthesised by the of WO9616051 for the corresponding 3-butyl-3-ethyl analogue; 0.400 g, 0.927 mmol) in MeCN (10 ml). The suspension was heated under reflux overnight before most of the solvent was removed under reduced pressure. The crude product was extracted (DCM/H2O) and filtered through a short silica-column (DCM:EtOAc-1:4) to give the title compound 0.476 g (99%). NMR (400 MHz 0.65-0.85 (m, 6H), 0.95-1.65 (m, 8H), 3.00-3.15 (m, 2H), 3.50-3.80 (m, 2H), 3.70-3.80 (s, 3H), 5.60 (s, 1H), 5.65 (d, 1H), 7.00-7.60 (m, 17H), 8.05-8.20 (d, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=2)[CH2:3]1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]([N:2]2[CH2:3][CH:4]([O:6][C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=3)[CH2:5]2)=[O:16])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: Brc1ccc(OC2CNC2)nc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(Br)cn2)C1
Yield: 37 %

Procedure:
This compound was prepared by the method outlined for example 5 step 3. Thus 2-(Azetidin-3-yloxy)-5-bromo-pyridine hydrochloride (2.0 g, 7.53 mmol) was reacted with 4-nitrophenyl chloroformate to afford the title compound (1.11 g, 37%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:15][CH:14]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[CH2:13]4)[S:8][C:6]=3[N:7]=[C:2]([NH:28][C:29]3[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Reactant: Nc1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ccccc1Nc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Yield: 48.1 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)-thiazolo[5,4-d]pyrimidine (500 mg, 1.22 mmol), 1,2-diaminobenzene (300 mg, 2.77 mmol), palladium acetate (80 mg, 0.36 mmol), BINAP (110 mg, 0.18 mmol) and cesium carbonate (600 mg, 1.84 mmol) in 1,4-dioxane (5 mL)) was purged with argon gas then subjected to microwave irradiation at 150° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (25 g), washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:2 M NH3 in MeOH 100:0 to 99:1 to 98:2 to 97:3) to afford N1-(7-morpholino-2-((3-morpholinoazetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-5-yl)benzene-1,2-diamine as a white solid (283 mg, 48%). LCMS (Method H): RT=2.40 min, [M+H]+ 483.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(O)C.[BH4-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:22]([C:23]([F:26])([F:25])[F:24])[OH:27])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(C(=O)C(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(C(O)C(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a stirred mixture of 1.9 g (0.005 mole) of 1-[4,5-bis(4-methoxyphenyl)-1H-pyrrol-2-yl]-2,2,2-trifluoro-1-ethanone and 25 ml ethanol at 0° was added 0.4 g (0.01 mole) of sodium borohydride all at once. The mixture was stirred at 0° 0.5 hour, then at room temperature 1 hour. The mixture was chilled in an ice bath and 40 ml of 1N hydrochloric acid was added dropwise. The mixture was poured into water and extracted with methylene chloride. The organic layers were dried and concentrated. The crude solid was triturated with methylcyclohexane and collected to give 1.6 g of product, m.p. 84°-86°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 0.236 mmol) was dissolved in dichloromethane (2.0 mL). Pyridine (2.0 mL) was added followed by benzoyl chloride (41 uL, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to give N1-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]benzamide (64 mg, 0.144 mmol). 1H NMR (CDCl3-d) δ 2.12 (m, 4H), 3.67 (m, 2H), 3.99 (s, 3H), 4.17(m, 2H), 4.99 (m, 1H), 7.03(s, 1H), 7.04 (s, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.53 (m, 3H), 7.94(d, J=7.8 Hz, 1H), 8.33 (s, 1H), 8.58 (s, 1H), 8.63 (d, J=8.2 Hz, 1H). LC/MS: MH+=444.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:25]=[CH:24][C:18]3[N:19]([CH3:23])[C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH3:23])[C:20](=[O:22])[O:21][C:17]=4[CH:16]=3)[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[CH:30][C:29]=1[F:28])=[O:36]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)oc(=O)n2C)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)oc(=O)n4C)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
The title compound was prepared in analogy to Example 117 from 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 133, step 3) by Suzuki coupling with 3-fluoro-4-methoxycarbonylphenylboronic acid [CAS Reg. No. 505083-04-5]. MS (neg. ion, m/e)=536.3 [(M−H)−].
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][O:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][C:21]([NH:23][CH3:24])=O)[CH:17]=2)[NH:12][N:11]=1.FC(F)(F)C(O)=O.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:8][O:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21][NH:23][CH3:24])[CH:17]=2)[NH:12][N:11]=1
Reactant: CNC(=O)CC(c1ccccc1)c1ccc2[nH]nc(OC)c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CNCCC(c1ccccc1)c1ccc2[nH]nc(OC)c2c1

Procedure:
[3-(3-Methoxy-1H-indazol-5-yl)-3-phenyl-propyl]-methyl-amine CCXIII was prepared as a trifluoroacetate from 3-(3-methoxy-1H-indazol-5-yl)-N-methyl-3-phenyl-propionamide and trifluoroacetic acid using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=297.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C@H:12]([CH3:37])[CH2:13][CH2:14][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:27]=2[Cl:36])[CH2:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.O>C1COCC1>[Cl:36][C:27]1[C:28]([C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:15]([CH2:16][C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[CH2:14][CH2:13][C@@H:12]([CH3:37])[O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(O[C@H](C)CCN(Cc2cccc(C(F)(F)F)c2Cl)C[C@@H](C)c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](CCN(Cc1cccc(C(F)(F)F)c1Cl)C[C@@H](C)c1ccccc1)Oc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.1 %

Procedure:
A solution of 2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}phenyl)acetic acid methyl ester (20 mg, 0.036 mmol) in THF (1 ml) at 0° C., was treated with LiAlH4 (100 uL of a 1N solution in THF), and the reaction was stirred at 0° for 45 minutes. Ethyl acetate (1 ml) was added, the reaction warmed to RT, and water (2 ml) was added. The mixture was extracted with ethyl acetate. The organic extracts were dried and the solvent removed. The residue was chromatographed over silica gel (hexane/Ethyl acetate:3/7) to give the title compound as a pure oil (15 mg, 91%). MS (ESI) 520.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](O)(=[O:19])[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClC(Cl)(Cl)C.C(C1CC(=CN(C)C)C=C(C(C)(C)C)C=1O)(C)(C)C>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: O=C(O)c1ccc(OCCCCO)cc1
Reactant: C=CC(=O)O
Agent: CN(C)C=C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)(Cl)Cl
Solvent: O
Product: C=CC(=O)OCCCCOc1ccc(C(=O)O)cc1
Yield: 63.2 %

Procedure:
276.6 g of 4-chlorobutyl acetate (1.8 mol) were added to a solution of 249 g of ethyl 4-hydroxybenzoate (1.5 mol), 3 g of potassium iodide (0.018 mol) and 248 g of potassium carbonate (1.8 mol) in 2 l of DMF, and the mixture was stirred at 90° C. for 11 hours. The reaction mixture was poured into 5 l of ice-water, and the precipitate was filtered off with suction and washed with 4 l of ice-water. The crude product was dissolved in 3 l of ethanol, potassium hydroxide (400 g) was added, and the mixture was refluxed for 3 hours. The reaction mixture was poured into 6 l of ice-water and acidified using concentrated hydrochloric acid, and the precipitate was filtered off. The precipitate was washed with water until neutral and then dried, giving 282.1 g of 4-(4′-hydroxybutoxy)benzoic acid (yield 89%). b) A solution of 282 g of 4-(4′-hydroxybutoxy)benzoic acid (1.34 mol), 230 ml of freshly distilled acrylic acid (3.35 mol), 0.3 g of 2,6-di-tert-butyl-4-(dimethylaminomethylene)phenol (Ethanox® 703) and 23.7 g of p-toluenesulfonic acid in 1.1 liter of 1,1,1-trichloroethane was refluxed for 10 hours on a water separator. The reaction mixture was cooled to 60° C.-70° C. and stirred into 2.5 l of petroleum ether, and the precipitate was filtered off. After washing with petroleum ether, the precipitate was dried for 24 hours at room temperature under reduced pressure, giving 223.7 g of 4-(4′-acryloxybutoxy)benzoic acid (yield 60%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5]1.[C:28]([N:32]=[C:33]=[O:34])([CH3:31])([CH3:30])[CH3:29].CO>C(Cl)Cl>[C:28]([NH:32][C:33](=[O:34])[NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=2)[CH2:8][CH2:9]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: CC(C)(C)N=C=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)NC(=O)NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 8 h

Procedure:
A solution of N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (25 mg, 0.063 mmol) in CH2Cl2 (1.5 mL) was treated with t-butyl isocyanate (30 mg, 0.13 mmol). The mixture was stirred overnight, treated with MeOH (1 mL). The solvent was removed in vacuo. The residue was purified by HiTOPs.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.Br[C:30]1[CH:55]=[CH:54][C:33]([CH2:34][CH2:35][N:36]([CH3:53])[C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH2:49][CH3:50])(=[O:48])=[O:47])=[C:42]([C:51]#[N:52])[CH:41]=2)=[O:38])=[CH:32][CH:31]=1>>[C:51]([C:42]1[CH:41]=[C:40]([NH:39][C:37](=[O:38])[N:36]([CH2:35][CH2:34][C:33]2[CH:54]=[CH:55][C:30]([B:25]([OH:27])[OH:26])=[CH:31][CH:32]=2)[CH3:53])[CH:45]=[CH:44][C:43]=1[S:46]([CH2:49][CH3:50])(=[O:48])=[O:47])#[N:52]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(Br)cc2)cc1C#N
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(B(O)O)cc2)cc1C#N
Yield: 78 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 25B (950 mg, 2.1 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 25C (679 mg, 78%) as an white solid. MS (ESI) m/z 415.93 (M+H)+.