Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[S:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[S:12][CH:11]=2)=[O:9])[CH2:2][CH2:3]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1csc(-c2cn[nH]c2)c1)N1CCCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
[1,4]Diazepan-1-yl-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone (0.075 g, 0.27 mmol) was dissolved in DCM (30 mL) and cooled in an ice-bath before addition of triethylamine (0.082 g, 0.82 mmol) and methanesulfonyl chloride (0.038 g, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the residue taken up in methanol (2.5 mL) and treated with sodium hydroxide (1 M, 0.3 mL). After 1 hour the solvent was removed and the crude material was purified by HPLC, eluting with 5%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were combined and freeze-dried to give the title compound (0.045 g). LCMS m/z 355.14 [M+H]+ R.T.=5.95 min (Analytical Method 2).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][N:12]3[CH3:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[N:1]1([C:6]2[CH:14]=[C:13]3[C:9]([C:10]([C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:11][N:12]3[CH3:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cn1ccc2ccc(-n3ccnc3)cc21
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C(=O)c1cn(C)c2cc(-n3ccnc3)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 116.1 %

Procedure:
6-Imidazol-1-yl-1-methyl-1H-indole (0.90 g, 4.56 mmol ) was dissolved in CH2Cl2 (2 mL) and cooled at 0° C. Methyl chlorooxoacetate (1.3 mL, 14 mmol) was added. Stirring was continued for 2 h at 0° C. and more methyl chlorooxoacetate (0.4 mL, 4.3 mmol) was added. After an additional 2 h, the solvent was removed. The residual solid was taken up in ether, filtered and washed well with ether to give crude methyl (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)glyoxylate (1.50 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](I)[C:9]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:5]=[O:6].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][O:15][CH2:14][CH2:13][O:12][CH2:11][O:10][C:9]1[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:2]1[CH:3]=[CH:4][CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: COCCOCOc1c(I)cc(C=O)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: O
Product: COCCOCOc1c(-c2ccccc2)cc(C=O)cc1-c1ccccc1
Yield: 57 %

Procedure:
The tile compound was prepared according to the procedure in Example 2, step 3 using 3,5-diiodo-4-(2-methoxyethoxymethoxy)benzaldehyde (4.029 g, 8.721 mmol), phenylboronic acid (2.339 g, 19.19 mmol), palladium(II) acetate (39.16 mg, 0.174 mmol) in DME:H2O. Purification on Biotage KP-Sil eluting with 15% EtOAc/pet. ether gave 1.803 g, (57%) of the title compound. 1H NMR (DMSO-d6) δ2.78-2.82 (m, 2 H), 2.89-2.92 (m, 2 H), 3.01 (s, 3 H), 4,42 (s, 2 H), 7.40-7.54 (m, 6 H), 7.62∝7.65 (m, 4 H), 7.91 (s, 2 H), 10.06 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:10]2[CH2:14][N:13]([C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:12](=[O:23])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1([CH:10]2[CH2:14][N:13]([C@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:12](=[O:23])[CH2:11]2)[CH2:7][CH2:8][CH2:9]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1(C2=CC(=O)N([C@@H](C)c3ccccc3)C2)CCC1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)C1(C2CC(=O)N([C@@H](C)c3ccccc3)C2)CCC1
Yield: 72.6 %

Procedure:
4-(1-Ethoxycarbonylcyclobutyl)-1-[(S)-1-phenylethyl]-3-pyrrolin-2-one (9.57 g, 31 mmol) was dissolved in ethanol (150 ml), and the solution was mixed with platinum oxide (230 mg) and stirred for 18 hours in a hydrogen atmosphere. After completing the reaction, the reaction solution was filtered and concentrated, and the resulting residue was applied three times to a silica gel chromatography column and eluted with an eluant of n-hexane:ethyl acetate=1:1, to thereby obtain optical isomer A (2.3 g, 24%) and optical isomer B (7.1 g, 74%) of the title compound each in an oily form.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([NH:7][O:8][CH3:9])=[O:6].[N:14]([O-])=O.[Na+].[Sn](Cl)Cl>O1CCOCC1.O.Cl>[NH:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([NH:7][O:8][CH3:9])=[O:6])[NH2:14]
Reactant: CONC(=O)c1ccc(C)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CONC(=O)c1ccc(C)c(NN)c1
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
To a stirred solution of 3-amino-4-methylbenzoic acid 1 (5.64 g, 31.2 mmol, 1.0 eq) in 100 mL of dioxane and 100 mL of water at 0° C. was added 100 mL of conc. HCl followed by the portionwise addition of sodium nitrite (2.82 g, 40.9 mmol, 1.1 eq) as a solid at a rate to control gas evolution and foaming over 45 minutes. A clear brown solution resulted. Anhydrous tin(II)chloride (15.62 g, 83.7 mmol, 2.25 eq) was dissolved in conc. HCl (25 mL) and added dropwise over 25 mL at 0° C. After 1 hour, the precipitate was filtertered and washed with dioxanes then dried under vacuum to provide 3-hydrazino-4-methyl-benzoic acid hydrochloride 2 as a tan solid (4.98 g, 66%): HPLC (4 minute gradient) tR 0.97 min; MS m/z 167 [M+H]+; 1H (300 MHz, DMSO-d6) δ 10.03 (s, 1 H, COOH), 7.89 (s, 1 H), 7.51 (s, 1 H), 7.27 (d, J=8.0, 1 H), 3.38 (s, 3 H, NHNH2), 2.23 (s, 3 H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[N+:14]([O-])=O.[H][H]>CO.[Pd]>[NH2:14][C:3]1[CH:4]=[C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)C2CC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)C2CC2)cc1N
Yield: 94.8 %

Procedure:
N-(4-Methyl-3-nitrophenyl)cyclopropanecarboxamide (409 mg) was hydrogenated over 10% Pd/C (50% wet, 80 mg) at atmospheric pressure of hydrogen in MeOH (20 mL) for 5 hr. The catalyst was removed by filtration through Celite® pad and the filtrate was evaporated in vacuo to give N-(3-amino-4-methylphenyl)cyclopropanecarboxamide (335 mg).
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C1(C)C=CC=CC=1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]2[NH:27][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)=[CH:28][CH:29]=1)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccncc1
Yield: 15.9 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (3.0 g) and 4-nitrobenzylamine (2.2 g) were dissolved in toluene (40 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give tert-butyl 2-(4-nitrophenyl)-5-(4-pyridyl)imidazole-4-carboxylate (0.7 g), melting point not less than 280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C@:18]3([CH3:40])[CH2:23][C@@H:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20]([NH:28]C(=O)C4C=CC([N+]([O-])=O)=CC=4)=[N:19]3)[N:12]=2)=[O:9])=[N:6][CH:7]=1.N12CCCN=C1CCCCC2>CO>[NH2:28][C:20]1[O:21][C@H:22]([C:24]([F:25])([F:27])[F:26])[CH2:23][C@:18]([C:13]2[N:12]=[C:11]([NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH:16]=[CH:15][C:14]=2[F:17])([CH3:40])[N:19]=1
Reactant: C[C@@]1(c2nc(NC(=O)c3ccc(Cl)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccc([N+](=O)[O-])cc2)=N1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@]1(c2nc(NC(=O)c3ccc(Cl)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a suspension of 5-chloro-N-(5-fluoro-6-((4S,6S)-4-methyl-2-(4-nitrobenzamido)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)pyridin-2-yl)picolinamide (8b, 76 mg, 0.131 mmol) in MeOH (1.3 mL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (Aldrich, 254 μl, 1.701 mmol). The reaction mixture was stirred at 70° C. for 1 h. The reaction was diluted with MeOH and purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 16 min. The product containing fractions were combined and neutralized with aqueous saturated sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound as a white solid (39 mg, 12% yield over two steps). MS m/z=432 [M+H]+. Calculated for C17H14ClF4N5O2: 431.
Reaction SMILES: [Mg].[O:2]=[C:3]([CH2:8]C)[CH2:4][C:5](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:22]1([C:25]([OH:27])=O)[CH2:24][CH2:23]1.Cl>CO.CN(C)C=O>[CH:22]1([C:25](=[O:27])[CH2:8][C:3](=[O:2])[CH2:4][CH3:5])[CH2:24][CH2:23]1
Reactant: O=C(O)C1CC1
Reactant: CCC(=O)CC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg]
Solvent: CN(C)C=O
Solvent: CO
Product: CCC(=O)CC(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A stirred suspension of magnesium turnings (1.83 g, 75.0 mmol) in methanol (85 ml) was heated under reflux for 90 minutes. The suspension was cooled to room temperature and a solution of 3-ketopentanoic acid (17.4 g, 150.0 mmol) in methanol (15 ml) was added. The white suspension dissolved to give a pale yellow solution. The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give a pale yellow solid which was dissolved in N,N-dimethylformamide (50 ml). In a separate flask carbonyldiimidazole (13.4 g, 83.0 mmol) was added portionwise to a stirred solution of cyclopropanecarboxylic acid (6.46 g, 75.0 mmol) in N,N-dimethylformamide (150 ml) at room temperature under nitrogen. The reaction was stirred for 90 minutes and then the magnesium salt previously prepared was added dropwise. The reaction was stirred for 3 days and then poured into 1.0M hydrochloric acid (150 ml). The aqueous phase was extracted with ether (3×200 ml) and the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (90:10, by volume) to provide the title compound (9.33 g) as a yellow oil.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:17]1([C:15]([N:12]2[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]2)=[O:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C(=O)N2CCCC2)CC1
Reaction time: 4 h

Procedure:
(tert-Butoxy)-N-[1-(pyrrolidinylcarbonyl)(4-piperidyl)]carboxamide (2.0 g, 6.73 mmol) was dissolved in 40 mL dichloromethane and trifluoroacetic acid (15 mL, 201.94 mmol) were added. The reaction mixture was stirred for 4 hours. The solvent was evaporated to give the product as a light brown semi-solid, which was used directly for the next step. (2.09 g, 6.73 mmol, 100%).
Reaction SMILES: [O:1]=[C:2]1[C:13]2[C:14]3[C:6](=[C:7]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[NH:8][C:9]=3[CH:10]=[C:11]([NH:15][C:16](=[O:43])[CH2:17][CH2:18][C:19]3[N:20]=[CH:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:23]=3)[CH:12]=2)[CH:5]=[N:4][NH:3]1.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[NH:22]1[CH:23]=[C:19]([CH2:18][CH2:17][C:16]([NH:15][C:11]2[CH:12]=[C:13]3[C:2](=[O:1])[NH:3][N:4]=[CH:5][C:6]4=[C:7]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[NH:8][C:9]([CH:10]=2)=[C:14]34)=[O:43])[N:20]=[CH:21]1
Reactant: O=C(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1c[nH]cn1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 62 %

Procedure:
Preparation of example 52 from the title compound of Example 51 (32 mg, 0.050 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. (Deprotection of trityl group was effected using the same conditions as for tert-butoxycarbonyl deprotection.) Isolation, also in an analogous manner, additionally included recrystallization from methanol/ethyl acetate and diethyl ether to afford the title compound (16 mg, 0.031 mmol) as a yellow powder in 62% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)=[O:12])[CH:3]=1>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)=[O:12])[CH:3]=1
Reactant: Nc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1N

Procedure:
Prepared analogously to example 83d by hydrogenation of 4-amino-5-nitro-N-(4-trifluoromethyl-pyridin-2-yl)-picolinamide using palladium/charcoal 10% in methanol and THF.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:16][O:17][CH2:18][CH:19]=[CH2:20])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[OH-].[Li+].Cl>C(O)C>[CH2:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:21])=[O:2])[CH2:16][O:17][CH2:18][CH:19]=[CH2:20])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CCOC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve N-(benzyloxycarbonyl)-O-2-propenyl-L-serine methyl ester (21.7 mmol) in ethanol (150 mL. Add 1N lithium hydroxide (50 mL) and stir overnight at room temperature. Reflux for 1 hour, cool to -10°, carefully adjust to pH 4 with 1N hydrochloric acid and stir for 1 hour. Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo to give N-(benzyloxycarbonyl)-O-2-propenyl-L-serine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:28]([NH2:29])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1.[H-].[Na+].[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:28]([NH:29][C:39]([NH:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)Nc3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 6-(2,6-dichlorophenyl)-N2 -(4-diethylamino-butyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 53 in DMF (15 mL) was added one equivalent of 60% sodium hydride suspension (0.93 g). After stirring for approximately 1 hour at room temperature, one equivalent of phenyl isocyanate (0.275 g) was added, and the reaction was monitored by thin layer chromatography. After approximately 24 hours, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, and this solution was washed several times, first with water and then a saturated solution of sodium chloride. The ethyl acetate layer was dried with magnesium sulfate and concentrated in vacuo. Chromatography of the residue over silica gel using ethyl acetate:methanol:triethylamine (90:10:1) followed by ethyl acetate:ethanol:triethylamine (9:2:1) gave 0.8461 g of the title compound 1-[6-(2,6-dichlorophenyl)-2-(4-diethylamino-butylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-phenyl-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH) M+ +H=552 (Base), 433; mp 81-87.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH2:32])=[O:30])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3)sc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(Oc3ccc(/C=C/C(N)=O)cc3)c(-c3ccc(F)cc3)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
(E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (48 mg, 0.115 mmol) was dissolved in DMF (3.00 mL). The vial was charged with HATU (65.6 mg, 0.173 mmol), DIEA (0.060 mL, 0.345 mmol), and NH4Cl (6.16 mg, 0.115 mmol). The reaction mixture was stirred for 10 min at room temperature. The reaction was quenched with sat. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated by vacuum to afford to crude product. The crude material was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (41 mg, 0.098 mmol, 85% yield) as a pale orange solid. 1H NMR (400 MHz, CD3OD) δ ppm==3.77 (s, 3 H) 6.40 (d, J=15.66 Hz, 1 H) 6.78-6.90 (m, 3 H) 6.95-7.06 (m, 2 H) 7.16 (d, J=8.59 Hz, 1 H) 7.29-7.49 (m, 4 H) 7.55-7.69 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[C:22][C:23]4[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=4)[CH:19]=3)[O:14][C:13]([CH3:35])([CH3:34])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[C:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=4)[CH:19]=3)[O:14][C:13]([CH3:35])([CH3:34])[CH:12]=2)=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CC(C)(C)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)C=C(c2ccc(C(C)(C)C)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc2O1
Temperature: 35 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of ethyl 4-[[4-(4-(1,1-dimethylethyl)phenyl)-2,2-dimethyl(2H)-chromen-6-yl]-ethynyl]-benzoate (Compound 269, 72.0 mg, 0.155 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 50.0 mg (74%) the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.00 (2H, d, J=8.3 Hz), 7.57 (2H, d, J=8.3 hz), 7.51 (2H, d, J=8.3 Hz), 7.41 (1H, dd, J=2.0, 8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 7.19 (1H, d, J=2.0 Hz), 6.91 (1H, d, J=8.3 Hz), 5.78 (1H, s), 1.49 (6H, s), 1.35 (9H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][NH:24][CH3:25]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:25])[CH3:23])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Reactant: CNC
Product: CN(C)CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and dimethylamine were converted to yield {4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine as white semisolid, MS: 344 (MH+).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:37][C:38]([F:48])([F:47])[C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH2:43]>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:43][CH2:42][C:41]4[CH:44]=[CH:45][CH:46]=[C:39]([C:38]([F:47])([F:48])[F:37])[CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccc(C(F)(F)F)c4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3-trifluoromethylbenzylamine, m.p. 171-173° C. MS [(+)ESI, m/z]: 592 [M+H]+
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH2:29])[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.Cl.CI.[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:31][C:2]([F:1])([F:30])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:29][CH3:35])[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(N)(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC1(C(=O)Nc2ccc(OC(F)(F)F)cc2)CCN(S(=O)(=O)c2ccc(C)cc2)CC1

Procedure:
A mixture of 42 mg (0.08 mmol) 4-Amino-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide; hydrochloride (example 80) and 96 mg (0.68 mmol) methyl iodide and 17.6 mg (0.128 mmol) potassium carbonate in 2 mL DMF was heated to 40° C. for 1.5 h. The mixture was filtered and the filtrate was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 9.6 mg (24%) of the title compound. MS (m/e): 472.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][C:5]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)(O)[CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:14][C:2]1([F:1])[CH2:7][CH2:6][C:5]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)=[CH:4][CH2:3]1
Reactant: OC1(c2cn[nH]c2)CCC(F)(F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FC1(F)CC=C(c2cn[nH]c2)CC1
Yield: 82.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 99b by using the 4,4-difluoro-1-(1H-pyrazol-4-yl)cyclohexanol (0.25 g, 1.24 mmol) prepared in Example 143a, p-toluenesulfonic acid monohydrate (120 mg, 0.62 mmol) and toluene (3.0 mL), to yield the title compound (189 mg, 83%) as a colorless solid.