Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42]>>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure F, 1-{6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}ethanone (30 mg, 0.0.77 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (44 mg, 0.154 mmol) to afford the desired product (29 mg, 80%) as a yellow solid: 1H NMR (500 MHz, CD3OD TFA-d) δ 9.13 (s, 1H), 8.48 (s, 1H), 8.30 (dd, J=8.7, 1.8 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.77 (s, 2H), 4.66-4.62 (m, 1H), 3.50-3.46 (m, 1H), 2.91 (s, 6H), 2.75 (s, 3H), 2.59-2.55 (m, 2H), 2.34-2.30 (m, 2H), 1.92-1.84 (m, 4H); ESI MS m/z 472 [C25H27Cl2N3O2+H]+; HPLC 98.0% (AUC), tR=9.78 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]([CH:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18])([CH3:15])[CH3:14].[CH3:22][O:23][CH2:24]Cl>C1COCC1>[CH:13]([C:16]1([CH2:22][O:23][CH3:24])[CH2:21][CH2:20][O:19][C:17]1=[O:18])([CH3:15])[CH3:14]
Reactant: COCCl
Reactant: CC(C)C1CCOC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCC1(C(C)C)CCOC1=O
Temperature: -70 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of diisopropylamine (13.1 mL) in THF was treated dropwise with butyl lithium (58.4 mL of 1.6M solution in hexanes) at −10° C. Then the reaction mixture was cooled to −70° C. and treated dropwise with 2-isopropyl-γ-butyrolactone (9.30 mL) keeping the speed of the addition at such a rate that the temperature of the mixture remained below −60° C. After completion of the addition, the mixture was stirred for 3 h at −70° C., then warmed-up to −40° C. and treated dropwise at this temperature with chloromethyl methyl ether (7.50 mL). After that, the mixture was allowed to slowly warm-up to room temperature and stirred at this temperature for 80 h. The solvents were removed in vacuum and the residue was redissolved in dichloromethane, then washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 7.00 g (57%) of the title compound.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CS(O[CH2:18][C@H:19]1[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1)(=O)=O.O>CN(C=O)C>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:18][C@H:19]1[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 112.5 °C
Reaction time: 16 h
Yield: 86388.6 %

Procedure:
Potassium phthalimide (28.4 g 0.15 mol) was added to a solution of (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (37.7 g, 0.13 mmol) in DMF (256 mL). The resulting mixture was stirred at 110-115° C. for 16 hr, and then cooled to room temperature and poured into water (500 mL). The aqueous layer was extracted with CH2Cl2 (3×250 mL). The combined organic layers were then washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was diluted in hexanes (200 mL) and then stirred vigorously while adding slowly Et2O (100 mL). The oil turned into a solid, which was filtered on a Buchner funnel. The filter cake was washed with hexanes and dried under reduced pressure. The mother liquor was concentrated, and the crude residue purified by silica gel flash chromatography (10-60% EtOAc in hexanes) to produce a second crop of solid. Both solids were combined to provide the title compound (38.9 g, 88%). 1H NMR (300 MHz, CDCl3) δ ppm 1.45 (s, 9 H), 2.68-2.82 (m, 1H), 2.91-3.04 (m, 1H), 3.44 (dt, J=11.45, 2.81 Hz, 1H), 3.63-3.79 (m, 3H), 3.82-4.03 (m, 3H), 7.70-7.78 (m, 2H), 7.84-7.88 (m, 2H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[OH:31])=[CH:22][CH:21]=2)=[CH:16][C:15]=1[O:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)=[O:13])(=[O:10])=[O:9])(=O)C>CO.Cl>[ClH:38].[Cl:38][C:34]1[CH:33]=[C:32]([C@@H:30]([OH:31])[CH2:29][NH:28][CH2:27][CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:12]([NH:11][S:8]([CH2:7][CH2:6][CH2:5][OH:4])(=[O:10])=[O:9])=[O:13])=[C:15]([O:46][CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)[CH:16]=3)=[CH:21][CH:22]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Agent: Cl
Solvent: CO
Product: O=C(NS(=O)(=O)CCCO)c1ccc(-c2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)cc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.1 %

Procedure:
The mixture of 3-[[[[4′-[2-[(tert-butoxycarbonyl)-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylyl]carbonyl]amino]sulfonyl]-propyl acetate (269 mg) in hydrogen chloride methanol solution (10%, 2.7 ml) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was recrystallized from aqueous ethanol (50%) to give 4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-(cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4-biphenylcarboxamide hydrochloride (161 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8])=[CH:2]1>CO>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8])[C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8])[C:2]1=2
Reactant: CCCCCCCCCCCCOC(=O)C(C(=O)OCCCCCCCCCCCC)c1ccsc1
Solvent: CO
Product: CCCCCCCCCCCCOC(=O)C1(C(=O)OCCCCCCCCCCCC)c2ccsc2C(C(=O)OCCCCCCCCCCCC)(C(=O)OCCCCCCCCCCCC)c2ccsc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 50.2 %

Procedure:
In a two-necked flask under argon, a solution of Fe(ClO4)3 in methanol (320 mL) was prepared at 0° C. A dispersion of didodecyl 2-(thiophen-3-yl)malonate in methanol (120 mL) was added to the solution. After the resulting solution was stirred at 60° C. for 4 hours under argon, the solvent was evaporated under vacuum at room temperature. After water (100 mL) was added to the residue, the aqueous layer was extracted with CH2Cl2 (100 mL×2) and the organic layer was dried and concentrated. The crude product was purified by flash chromatography (eluent: CH2Cl2:hexane=3:2) to give tetradodecyl benzo[1,2-b:4,5-b′]dithiophene-4,4,8,8-tetracarboxylate (yield: 9.0 g, 50.2%). 1H NMR (CDCl3); 0.9 (12H, t), 1.3 (72H, m), 1.7 (8H, m), 4.2 (8H, t), 7.3 (2H, d), 7.4 (2H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].Cl.[NH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>CCOC(C)=O.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: COC(=O)CN
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The product of Example 48 (2.25 g mg, 5.0 mmol), methyl glycinate hydrochloride (3.13 g, 25.0 mmol), anhyd K2CO3 (3.45 g, 25.0 mmol) and NMP (25 mL) were stirred for 1 h at 60°. The reaction was diluted with EtOAc (200 mL), washed with 10% aq citric acid (2×25 mL), H2O (25 mL) and satd aq NaCl (40 mL) dried (Na2SO4) and concentrated. The resulting brown residue was filtered through a plug of silica (350 mL) (dichloromethane/methanol) to afford a brown foam. Trituration with Et2O afforded the title compound, methyl N-[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-oxopyrido[2,3-d]pyrimidin-2-yl]glycinate as a white solid. mp=212-213°.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[OH:20][CH:21]1[CH2:24][NH:23][CH2:22]1>>[OH:20][CH:21]1[CH2:24][N:23]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:22]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: OC1CNC1
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CC(O)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 3-hydroxyazetidine hydrochloride by the method described in Example 41. Colorless solid (78 mg, 73%). 1H NMR (DMSO-d6) 2.38 (s, 3H), 3.77-3.90 (m, 1H), 4.19-4.38 (m, 2H), 4.52-4.63 (m, 1H), 4.65-4.78 (m, 1H), 5.88 (d, J=5.9, 1H), 7.62 (d, J=4.0, 1H), 7.73 (d, J=4.0, 1H). 13C NMR 7.4, 58.9, 60.6, 62.5, 116.0 (q, J=2), 118.5 (q, J=271), 130.3, 130.5, 131.0, 140.2, 153.2 (q, J=40), 157.9, 160.8. 19F NMR −62.3. LC/MS 5.42 min, [M+1]+ 333.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:13][CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc(C(F)(F)F)cc1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-trifluoromethylaniline gave 2-chloro-5-fluoro-N4-(4-trifluoromethylphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.15 (d, 2.1 Hz), 7.80 (d, 2H, J=7.1 Hz), 7.66 (d, 2H, J=9 Hz), 7.10 (bs, 1H); 19F NMR (CDCl3): −17682 and −44362; LCMS: purity: 91% and MS (m/z): 292 (MH+).
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[Na+].[O-:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]1([OH:23])C=CC=CC=1.[C]=O.O=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Pd].[O-2].[Mn+2]>[C:17](=[O:23])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-]c1ccccc1
Reactant: Oc1ccccc1
Agent: [Mn+2]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Using the same 100-ml reactor as in Examples 1 to 14, the reaction was carried out in the presence of 1000 mg of the above-mentioned supported catalyst (2.5% Pd/Manganese oxide) under the same conditions as in the examples, that is, in each case of the addition (Comparative Example 6) or no addition (Comparative Example 7) of disodium phenoxide, 50.0 g of phenol and 1000 mg of tetra-n-butylammonium bromide were charged, and the reaction was carried out at a reaction temperature of 80° C., under a reaction pressure of 10 bar, at a flow rate of carbon monoxide of 500 ml/min, at a flow rate of oxygen of 25 ml/min and for a reaction time of 2 hours. The obtained results are shown in the following Table 2 together with other comparative examples.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:11][CH2:10]2)[C:3]=1[NH2:12].[CH2:13]([C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:12][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[N:23][C:15]=2[CH2:13][CH3:14])=[C:4]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]=[CH:6][N:7]=1
Reactant: CCc1ncccc1C(=O)Cl
Reactant: Nc1c(Cl)ncnc1NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ncccc1C(=O)Nc1c(Cl)ncnc1NC1CC1
Temperature: 0 °C

Procedure:
6-Chloro-N-cyclopropylpyrimidine-4,5-diamine (cf. Journal of Combinatorial Chemistry (2003), 5(5), 653-659) (3.0 g, 16.2 mmol) was initially charged in a mixture of methylene chloride (12.20 ml) and pyridine (3.94 ml). The suspension was cooled to 0° C., and solid 2-ethylnicotinoyl chloride (1.2 eq) was added. The reaction mixture was allowed to warm to room temperature and stirred until the reaction had gone to completion. 10 ml of methylene chloride were then added, the suspension turning into a solution. About 10 ml of semisaturated NaHCO3 solution were added to the organic phase whilst the mixture was stirred vigorously in a flask using a magnetic stirrer; poorly soluble crystals (product) precipitated and were filtered off with suction, washed 3× with a little water and 3× with n-heptane and dried.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br)#[N:2].Cl.[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH2:16].C([O-])(O)=O.[Na+].[Na+].[I-]>CS(C)=O.C1COCC1.CCOC(C)=O.O>[CH3:12][O:13][C:14](=[O:17])[CH2:15][N:16]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=1)[CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN(Cc1cccc(C#N)c1)Cc1cccc(C#N)c1
Temperature: 25 °C

Procedure:
m-Cyanobenzyl bromide (2.35 g, 12.0 mmol) was slowly added to a solution of glycine methyl ester hydrochloride (0.63 g, 5.0 mmol), NaHCO3 (1.4 g, 17.0 mmol) and NaI (0.37 g, 2.4 mmol) in DMSO (5 mL) and THF (20 mL). The reaction was heated to reflux for 2 hours, cooled to room temperature and diluted with EtOAc (50 ml) and water (40 mL). The organic phase was washed with water (3×40 mL), saturated aqueous NaCl (40 mL), dried (Na2SO4), filtered and concentrated in vacuo to give N,N-Bis(m-cyanobenzyl)glycine methyl ester as a colorless oil of sufficient purity for subsequent reactions. Additional purification can be achieved by extraction into dilute aqueous acid, basification and extraction in an organic solvent. 1H NMR (200 MHz, CDCl3): δ3.39, s, 2H; 3.71, s, 3H; 3.86, s, 4H; 7.39-7.73, m, 10H.
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17]([CH:19]1[CH2:21][CH2:20]1)=[O:18])=[C:5]2C.[CH2:28]([NH2:31])[C:29]#[CH:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17]([CH:19]1[CH2:20][CH2:21]1)=[O:18])=[C:5]2[NH:31][CH2:28][C:29]#[CH:30]
Reactant: C#CCN
Reactant: Cc1c(C(=O)C2CC2)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)c(OS(=O)(=O)O)c12
Product: C#CCNc1c(C(=O)C2CC2)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 71.9 %

Procedure:
6-Chloro-3-cyclopropanecarbonyl-4-methylsulfoxy-8-trifluormethyl-2-quinolinone (377 mg, 1 mmol) and propargylamine (55 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (265 mg, yield: 72%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:11][CH2:12][OH:13])[CH2:10][CH2:9][NH:8][CH2:7]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:11][CH2:12][OH:13])[CH2:10][CH2:9][N:8]([C:19](=[O:20])[C:18]2[CH:17]=[C:16]([O:15][CH3:14])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=2)[CH2:7]1
Reactant: OCCC1(c2cccs2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCO)(c3cccs3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-(thiophen-2-yl)-pyrrolidin-3-yl]-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:27]([NH:28][CH3:29])=[N:26][C:7]2[N:8]([CH2:15][C@@H:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17])[C:9]3[C:14]([C:6]=2[CH:5]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:3].C(O)(C(F)(F)F)=O.NC1C(C(N)=O)=CC2C3C(=CC=CC=3)N(C[C@@H](N)C)C=2N=1>>[NH2:18][C@@H:16]([CH3:17])[CH2:15][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:5]=[C:4]([C:2]([NH2:1])=[O:3])[C:27]([NH:28][CH3:29])=[N:26][C:7]1=2
Reactant: CNc1nc2c(cc1C(N)=O)c1ccccc1n2C[C@H](C)NC(=O)OC(C)(C)C
Agent: C[C@H](N)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc2c(cc1C(N)=O)c1ccccc1n2C[C@H](C)N
Yield: 35 %

Procedure:
tert-butyl {(1S)-2-[3-(aminocarbonyl)-2-(methylamino)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate xxxii-a (20 mg, 0.051 mmol) was deprotected according to the TFA procedure detailed in the preparation of 30 to afford the title compound as the trifluoroacetate salt (45, 7 mg, 35%). NH4OAc standard conditions. DAD Retention time=5.33 min. M+H=298. 1H NMR (300 MHz, CDCl3): δ 9.04 (br s, 1H), 8.76 (s, 1H), 8.02 (br s, 4H), 7.82 (d, J=7.9 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.35 (br dd, J=7.3, 7.3 Hz, 1H), 7.23 (br dd, J=7.3, 7.3 Hz, 1H), 4.48-4.44 (m, 1H), 3.04 (s, 3H), 3.57-3.52 (m, 2H), 1.21 (d, J=6.1 Hz, 3H).
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11]Br)C.[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH3:15].NC1C=CC=CC=1>>[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:11][C:6]3[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:4]2=[O:13])=[CH:24][CH:25]=1)[CH3:15]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: CCOC(=O)c1ccccc1CBr
Solvent: Nc1ccccc1
Product: CCOC(=O)C=Cc1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
By using 2-bromomethyl-benzoic acid ethyl ester and 4-aminocinnamic acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 3-[4-(1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-acrylic acid ethyl ester (Compound 23) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([OH:17])=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:29]1([C:34]2[CH:39]=[C:38]([CH2:40][NH2:41])[CH:37]=[C:36]([C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=3)[N:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2([C:15]([NH:41][CH2:40][C:38]3[CH:37]=[C:36]([C:42]4[CH:43]=[CH:44][C:45]([C:48]([F:51])([F:49])[F:50])=[CH:46][CH:47]=4)[N:35]=[C:34]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[CH:39]=3)=[O:17])[CH2:13][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: O=C(NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A solution of acid 15C (0.50 g, 1.75 mmol) in THF (25 mL) was added with DEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at room temperature for 5′. Then [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (0.61 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water (40 mL) was added to the residue that is extracted with EtOAc (3×25 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a pale orange solid (0.21 g) after crystallization from a mixture of ethyl ether/petroleum ether. Yield=22%, 1HNMR (DMSO, 200 MHz) δ 0.71 (m, 2H), 1.09 (m, 2H9, 1.96 (m, 4H), 3.38 (m, 4H), 4.18 (d, 2H, J=6.1), 6.33 (s, 1H), 6.46 (s, 1H), 7.47-7.38 (m, 4H), 7.88-7.80 (m, 4H), 8.37 (t, 1H), 8.71 (bs, 1H); [M+1] 562.58 (C27H26F4N4O3S requires 562.16).
Reaction SMILES: [Br-:1].[Na+].Cl[O-].[Na+].[CH3:6][C:7]1[CH:12]([CH2:13][CH2:14][C:15]([CH3:17])=[O:16])[C:11]([CH3:19])([CH3:18])[CH2:10][CH2:9][CH:8]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C(Cl)Cl>[Br:1][CH:8]1[C:7](=[CH2:6])[CH:12]([CH2:13][CH2:14][C:15](=[O:16])[CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10][CH2:9]1
Reactant: [Br-]
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=C1C(Br)CCC(C)(C)C1CCC(C)=O
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
A solution of sodium bromide (6.17 g) in water (10 ml) and commercial bleach (31.2 ml of a solution of sodium hypochlorite) were stirred together for 5 minutes and a solution of dihydro-α-ionone (3.88 g) in methylene chloride was added. Then a solution of potassium phosphate (monobasic) (5.44 g) in water (30 ml) was added during 30 minutes. After stirring for 50 minutes at 25° a solution of sodium bromide (2.05 g) and commercial bleach (10 ml) was added, followed by a solution of potassium phosphate (monobasic) (2.72 g) in water (10 ml) and the reaction mixture stirred for 15 minutes at 25°. The methylene chloride solution was washed with sodium bicarbonate solution and the solvent evaporated to provide the crude product (5.86 g). Column chromatography gave 1.87 g of 4-(5-bromo-6-methylene-2,2-dimethylcyclohexyl)-2-butanone. NMR (CDCl3) δ0.93 (6H, s, >C(CH3)2), 0.9-2.6 (9H, m), 2.12 (3H, s, --COCH3), 4.6-5.1 (1H, m, >CHBr), 4.76 and 5.28 (2H, 2s, >C=CH2), 4.68 and 5.20 (2H, 2s, >C=CH2, minor isomer; isomer ratio 3/1). IR (film) νmax 2960, 1720, 1675, 1650, 1455, 1360.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:17])=O>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCCOc1ccc(C(=O)Cl)cc1

Procedure:
A solution of 5 g of para-n-butoxy benzoic acid is refluxed for 2 hours in 8 ml of thionyl chloride. The thionyl chloride is then distilled, followed by distillation under reduced pressure and under a dry nitrogen stream of the expected acid chloride. In this way para-n-butoxy benzoic acid chloride of the following formula is obtained: ##STR36##
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:12]N1C(=O)CCC1=O>CC(C)=O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[C:10]([I:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1c(Br)cnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Clc1c(Br)cnc2[nH]cc(I)c12
Temperature: 23 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (5.19 g, 22.4 mmol) and N-iodosuccinimide (5.55 g, 24.6 mmol) were suspended in 100 mL acetone. The mixture was stirred at 23° C. for 2 h and diluted with 150 mL water and 20 mL of saturated sodium thiosulfate solution. The precipitate was filtered and residual water was removed by dissolving the solids in dry benzene and followed by evaporation (2×100 mL) to yield 5-Bromo-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (7.68 g, 21.5 mmol, 96%). 1H NMR (500 MHz, DMSO-d6) δ 12.65 (bs, 1H), 8.45 (s, 1H), 7.87 (d, J=3 Hz, 1H). MS: m/z 356.8/358.8 (M+H+).