Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]([C@@H:13]([C@H:15]([C:17]([O-:19])=[O:18])[OH:16])[OH:14])([O-:12])=[O:11]>CO>[C:10]([C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14])([OH:12])=[O:11].[C:5](#[N:6])[C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: CO
Product: N#Cc1ccccc1
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
A procedure similar to Step C of Example 14 was used to couple 5-(4-chlorophenyl)-2,5-ethano-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-2-benzoazepine from Step B of Example 14 with 3-bromobenzonitrile. The desired coupling product was obtained and converted to the corresponding L-tartrate salt as in step C, except no methanol was used, to provide 34544-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzonitrile, L-tartrate salt (36 mg, 26%, AUC HPLC 97.8%) as an off-white solid: 1H NMR (CD3OD, 500 MHz) δ 7.98 (s, 1H), 7.93-7.91 (m, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.63-7.60 (m, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.5 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 6.49 (d, J=8.0 Hz, 1H), 4.87 (br s, 2H), 4.41 (s, 2.2H), 3.68-3.50 (m, 2H), 3.50-3.35 (m, 2H), 2.81-2.75 (m, 2H), 2.48-2.41 (m, 2H); ESI MS m/z 385 [M+H]+. Anal. Calcd. For C25H21ClN2.1.1C4H6O6.1.75H2O: C, 60.72; H, 5.39; N, 4.82. Found: C, 60.72; H, 5.22; N, 4.96.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:19]=[CH:20][C:21]([C:24]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1cc2c(s1)CCCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCCCc2sccc21

Procedure:
As described for Example 1, a solution of 2 mmol of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine, 5 mmol of triethylamine and 2.1 mmol of [1,1'-biphenyl]-4-carbonyl chloride in 10 ml of CH2Cl2 is stirred at room temperature for 16 hours to give the product as a solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:43])([CH3:42])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[CH:21]1[C@:12]([CH3:41])([C@@:13]3([CH3:40])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([C:32](=[O:39])[NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[CH3:46][O:47][C:48]([C:50]1[S:54][C:53](B(O)O)=[CH:52][CH:51]=1)=[O:49].C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:38][N:36]([CH3:37])[CH2:35][CH2:34][NH:33][C:32]([C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:40])([CH2:14][CH2:15]2)[C@@:12]2([CH3:41])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:42])([CH3:43])[C:7]([C:53]2[S:54][C:50]([C:48]([O:47][CH3:46])=[O:49])=[CH:51][CH:52]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[O:39]
Reactant: COC(=O)c1ccc(B(O)O)s1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
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: O
Solvent: COCCOC
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)s6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,11aR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (100 mg, 0.152 mmol), 5-(methoxycarbonyl)thiophen-2-ylboronic acid (36 mg, 0.228 mmol), tetrakis(triphenylphosphine)palladium(0) (5.2 mg, 0.0045 mmol) and sodium carbonate (48 mg, 0.456 mmol) in water (1 mL) and DME (1 mL) was heated up at 90° C. for 2 hours. The reaction mixture was quenched with distilled water, extracted with ethyl acetate (3×5 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a brown oil (60 mg, 32%). LCMS: m/e 647.63 (M−H)−, 2.67 min (method 1).
Reaction SMILES: [OH:1]S(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]([C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:24]=3)=[CH:21][CH:22]=2)=[CH:16][C:15]([CH2:33][C:34]#N)=[N:14]1.[C:36]([O-])([O-])=[O:37].[Na+].[Na+]>CO.O.O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]([C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:24]=3)=[CH:21][CH:22]=2)=[CH:16][C:15]([CH2:33][C:34]([O:37][CH3:36])=[O:1])=[N:14]1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(O)O
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CC#N)nn3-c3ccccc3Cl)s2)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Concentrated H2SO4 (4 mL) was added dropwise at 0° C. to a stirred solution of the [1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]acetonitrile (148 mg, 0.33 mmol) in a mixture of MeOH—H2O (10:1, 11 mL), and the resulting mixture was stirred at 90° C. overnight. The mixture was diluted with cold water, then basified with Na2CO3 solid, extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-40% 20% MeOH/DCM) to afford the title compound as a white solid (131 mg, 82%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.83-7.81 (m, 1H), 7.73-7.71 (m, 1H), 7.57-7.41 (m, 5H), 7.20 (d, 1H), 6.75 (d, 1H), 6.69 9s, 1H), 3.82 9s, 2H), 3.79 (s, 3H), 3.08 (s, 3H). MS(ES): 487 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]1([O:31][C:32]2[N:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[F:50][C:51]([F:64])([F:63])[C:52]1[NH:53][C:54]2[C:59]([CH:60]=1)=[CH:58][C:57]([CH2:61][NH2:62])=[CH:56][CH:55]=2>CN(C=O)C>[O:31]([C:32]1[N:37]=[CH:36][C:35]([C:38]([NH:62][CH2:61][C:57]2[CH:58]=[C:59]3[C:54](=[CH:55][CH:56]=2)[NH:53][C:52]([C:51]([F:64])([F:50])[F:63])=[CH:60]3)=[O:40])=[CH:34][CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)nc1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(Oc2ccccc2)nc1
Reaction time: 24 h
Yield: 16.7 %

Procedure:
To a stirred solution of HATU (121 mg, 0.319 mmol) in DMF (1 ml) was added 6-(phenyloxy)-3-pyridinecarboxylic acid (Maybridge; 51.5 mg, 0.239 mmol) in DMF (0.5 ml), followed by DIPEA (0.084 ml, 0.479 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 40 mg, 0.160 mmol) in DMF (1 ml). The solution was stirred for 24 hrs. DMF was removed using a rotary evaporator followed by addition of DCM and sodium bicarbonate solution. The mixture was poured through a phase separation cartridge, the organic layer evaporated to dryness and purified using MDAP to give the title compound as a white solid (11 mg);
Reaction SMILES: [C-:1]#[N:2].[Na+].O.C(O)C.Cl[CH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1>C(OCC)C>[C:1]([CH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1)#[N:2]
Reactant: [C-]#N
Reactant: C=Cc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: C=Cc1ccc(CC#N)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
As shown in the following Reaction 1a, 49.01 g of sodium cyanide (NaCN), 70.07 g of water and 50.96 g of ethanol were added into a 500 ml 4-neck flask equipped with a mechanical stir, and the temperature of the solution was elevated to 60° C. to completely dissolve NaCN. To the solution, 87.50 g of 4-chloromethylstyrene was slowly added and the reaction was carried out for 3 hours at the temperature of 60-70° C. After completion of the reaction, the solution was cooled to 40° C., 100 g of diethylether was added to the solution, and the diethylether layer was separated. The separated organic layer was extracted with 300 g of water three times. The water layer was extracted with 50 g of diethylether and the diethylether extract was added to the organic layer. The separated organic layer was dried with magnesium sulfate for one day, and then the organic solvent was removed using an evaporator to obtain 4-cyanomethylstyrene of deep purple color. The yield of the product was 80%.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)N>>[F:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:21]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)=[CH:20][C:19]=1[O:18][CH3:17]
Reactant: COc1cc(N)ccc1OCc1cccc(F)c1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Product: COc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1cccc(F)c1
Yield: 54 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (2.0 g, 8.96 mmol) and 3-methoxy-4-[(3-fluorobenzyl)oxy]aniline (2.67 g, 10.8 mmol) to give the title compound as a white solid (2.06 g, 54%); NMR Spectrum: 3.79 (t, 2H), 3.80 (s, 3H), 4.31 (t, 2H), 5.12 (s, 2H), 7.03 (d, 1H), 7.18 (m, 2H), 7.29 (m, 2H), 7.35 (d, 1H), 7.45 (q, 1H), 8.22 (s, 1H); Mass Spectrum: 426 (MH+).
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]#[C:7][C:8]([CH3:12])=[CH:9][CH2:10][OH:11])[CH:3]=[O:4].[H][H].N1C2C(=CC=CC=2)C=CC=1>C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-].C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:5][CH:6]=[CH:7][C:8]([CH3:12])=[CH:9][CH2:10][OH:11])[CH:3]=[O:4]
Reactant: [H][H]
Reactant: CC(C#CC=C(C)C=O)=CCO
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1
Solvent: c1ccc2ncccc2c1
Product: CC(C=O)=CC=CC(C)=CCO

Procedure:
The residue obtained (240 g.) is dissolved in 1800 ml. of acetone, treated with 300 ml. of N-sulfuric acid and allowed to stand at room temperature in a nitrogen atmosphere for 1 hour. Then the reaction mixture, after dilution with 4000 ml. of water, is taken up in ether. The ether extract is washed with sodium bicarbonate solution and water, dried over sodium sulfate, filtered, and evaporated. 170 g. of crude 2,6-dimethyl-8-hydroxy-2,6-octadien-4-in-1-al is obtained which can be purified through adsorption on aluminum oxide (activity II deactivated by the addition of 7 per cent water). A small portion is removed by washing with petroleum ether/ether mixture (4:1). By elution with a petroleum ether/ether mixture (3:2) there is obtained pure 2,6-dimethyl-8-hydroxy-2,6-octadien-4-in-1-al (Abs. Max. 312 mμ; E11 = 1200) (in 96 per cent ethyl alcohol). 125 g. of 2,6-dimethyl-8-hydroxy-2,6-octadien-4-in-1-al are dissolved in 600 ml. of toluene and hydrogenated until the cessation of hydrogen takeup after the addition of 15 g. of a lead/palladium-calcium carbonate catalyst and 2 ml. of quinoline in the usual manner. After filtration and evaporation of the solution, there is obtained 2,6-dimethyl-8-hydroxy-2,4,6-octatrien-1-al.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C:6]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:36].[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:5]4[N:4]([CH3:37])[C:3](=[O:36])[C@@H:2]([CH3:1])[O:7][C:6]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: O=C([O-])[O-]
Reactant: C[C@H]1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: C[C@H]1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.1 %

Procedure:
A solution of (R)-tert-butyl 1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.206 mmol) in DMF (2 ml) was added potassium carbonate (85 mg) and iodomethane (15p1, 0.247 mmol). The reaction mixture was stirred at room temperature for 16 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (Biotage, size: 25 g) eluted with ethyl acetate/cyclohexane (0-50%) to afford product (33 mg). 1H NMR (500 MHz, CDCl3): 7.19-7.32 (m, 10H), 4.96 (q, 1H), 3.39 (s, 3H), 2.43-2.48 (m, 4H), 2.04 (m, 1H), 1.80 (m, 1H), 1.70 (d, 3H), 1.24-1.36 (m, 9H).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:9]([C:17]2[N:22]=[CH:21][N:20]3[C:23](O)=[CH:24][CH:25]=[C:19]3[CH:18]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][CH2:30][Cl:31].CN(C)C=[O:35]>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:35][CH2:28][CH2:29][CH2:30][Cl:31])=[CH:14][CH:15]=2)[O:10][C:9]([C:17]2[N:22]=[CH:21][N:20]3[CH:23]=[CH:24][CH:25]=[C:19]3[CH:18]=2)=[CH:8]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccc(O)n3cn2)oc2ccccc12
Reactant: CN(C)C=O
Reactant: ClCCCBr
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2cc(OCCCCl)ccc12
Yield: 100 %

Procedure:
7-(3-Chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime was prepared in 100% yield using the method described in example 85A, starting from 7-Hydroxy-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 142B) and 1-bromo-3-chloropropane in dimethylformamide. The title compound was isolated as a brown solid.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=1[S:26](=[O:29])(=[O:28])[NH2:27]>C(N(CC)CC)C>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][N:2]2[CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:14][CH3:15])[CH2:6][CH2:7]2)=[O:22])=[CH:19][C:18]=1[S:26](=[O:28])(=[O:29])[NH2:27]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: COc1ccccc1N1CCN(N)CC1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(NC(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 1 g of 1-amino-4-(2-methoxyphenyl)piperazine and 1 ml of triethylamine was added 1.25 g of 4-chloro-3-sulfamoylbenzoyl chloride under stirring at room temperature. The reaction mixture was stirred at room temperature for 9 hours. The resulting precipitate was filtered, washed with water and recrystallized from ethanol to afford a title compound in a yield of 1.20 g (60%) as colorless needle crystals, mp 231°-233° C.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].C1[CH2:11][S:8](=[O:10])(=[O:9])[O:7]C1>CO>[SH:3][CH2:1][CH2:2][CH2:11][S:8]([O-:10])(=[O:9])=[O:7].[NH4+:4]
Reactant: O=S1(=O)CCCO1
Reactant: CC(N)=S
Solvent: CO
Product: O=S(=O)([O-])CCCS
Product: [NH4+]

Procedure:
A solution of 50.0 grams of thioacetamide and 81.5 grams of 1,3-propane sultone in 700 ml of methanol is refluxed at atmospheric pressure for 10 minutes. The reaction mixture is then concentrated by evaporation of solvent to 200 ml, and 600 ml of anhydrous diethyl ether is added. A white precipitate is formed, is collected by filtration and then is dissolved in 350 ml of ethanol. After drying and decolorizing with 4A molecular sieves* and charcoal, addition of anhydrous diethyl ether to the filtered solution, and refiltration, the yield is 59.7 g (50% of theoretical) of shiny white crystals of ammonium 3-mercaptopropanesulfonate having a melting point of 160°C. C3H11NO3S2Calculated % C, 20.8; H, 6.4; N, 8.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[O:17][CH2:18][C:19](=[O:26])[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[C:29]([CH:36]=O)=[CH:28]1.N1CCCCC1>C(O)C>[NH:27]1[C:35]2=[N:34][CH:33]=[CH:32][CH:31]=[C:30]2[C:29]([CH:36]=[C:18]2[O:17][C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=3)=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]2=[O:26])=[CH:28]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(NC(=O)OC(C)(C)C)cc2)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(NC(=O)OC(C)(C)C)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-({4-[(tert-butoxycarbonyl)amino]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.32 g, 0.88 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.88 mmol) in ethanol (5.0 mL), piperidine (0.18 mL, 1.8 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(tert-butoxycarbonyl)amino]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.095 g, y. 21%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18]C)=[O:17])[C:13](=[O:20])[C:12]([CH2:23][CH3:24])([CH2:21][CH3:22])[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].[OH-].[ClH:27]>C1COCC1.O>[ClH:27].[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:20])[C:12]([CH2:23][CH3:24])([CH2:21][CH3:22])[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)OC)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl [(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetate from Step C (43 mg, 0.126 mmol) in THF (0.75 mL) and H2O (0.25 mL) was added 1 N aqueous LiOH (0.139 mL, 0.139 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was adjusted to pH 4 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=327 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]3[CH3:27])[C:11]3[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[O:28]1[CH2:33]COCC1.C(N(CC)CC)C.C(Cl)(Cl)=O.[F:45][C:46]([F:50])([F:49])[CH2:47][NH2:48]>C1(C)C=CC=CC=1>[C:18]([N:15]1[CH2:16][CH2:17][C:11]2[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]3[CH3:27])=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:48][CH2:47][C:46]([F:50])([F:49])[F:45])=[O:28])=[CH:7][CH:6]=3)=[N:13][C:12]=2[CH2:14]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCc2c(nc(-c3ccc(N)cc3)nc2N2CCOC[C@@H]2C)C1
Reactant: C1COCCO1
Reactant: NCC(F)(F)F
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2c(nc(-c3ccc(NC(=O)NCC(F)(F)F)cc3)nc2N2CCOC[C@@H]2C)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Step 3—Synthesis of compound ux: (S)-1-(2-(4-aminophenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethanone (0.100 g, 0.000272 mol) in dry 1,4-Dioxane (2.00 mL, 0.0256 mol) was added Triethylamine (0.0416 mL, 0.000299 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.160 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added 2,2,2-trifluoroethylamine (0.1280 mL, 0.001627 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 9.01 (d, J=5.1, 1H), 8.21 (dd, J=8.8, 2.7, 2H), 7.52 (d, J=8.4, 2H), 6.82 (t, J=6.4, 1H), 4.74-4.43 (m, 2H), 4.16 (s, 1H), 4.00-3.85 (m, 3H), 3.64 (ddd, J=19.4, 16.7, 9.4, 6H), 3.43 (d, J=21.0, 2H), 2.76 (s, 1H), 2.63 (s, 1H), 2.12 (s, 3H), 1.33-1.22 (m, 3H). LC/MS-m/z+493.2 (M+H)+
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([O:14]C2CCCCO2)[CH:11]=[CH:12][CH:13]=1.[Br:21]CCBr>O1CCCC1.Cl>[Br:21][C:9]1[C:8]([O:7][CH3:6])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:14]
Reactant: BrCCBr
Reactant: COc1cccc(OC2CCCCO2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(O)c1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
33 mL (52.8 mMol) n-butyllithium (1.6 M in hexane) were added dropwise to a solution 10 gm (48.1 mMol) tetrahydropyran-2-yl 3-methoxyphenyl ether in 100 mL tetrahydrofuran over 15 minutes. After stirring for 2.5 hours at room temperature, the reaction mixture was cooled to 0° C. and then 4.6 mL (53.2 mMol) 1,2-dibromoethane were added dropwise. The reaction mixture was then allowed to stir at room temperature for about 14 hours. The reaction mixture was then diluted with 50 mL 1 N hydrochloric acid and was stirred for 1 hour. The aqueous phase was extracted with three 100 mL portions of diethyl ether. The organic phases were combined and extracted well with 5 N sodium hydroxide. These basic aqueous extracts were combined and cooled in an ice/water bath. The pH of this aqueous solution was adjusted to about 1 with 5 N hydrochloric acid and then extracted with three 100 mL portions of diethyl ether. These ether extracts were combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 10% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 2.91 gm (30%) of a residue which crystallized upon standing.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.[OH:20][CH2:21][CH2:22][NH2:23].C(N(CC)CC)C.[H][H]>C(#N)C.[C].[Pd].O>[OH:20][CH2:21][CH2:22][NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[NH2:17]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (0.50 g, 1.9 mmol) in acetonitrile (10 mL) was added 2-hydroxyethylamine (0.14 g, 2.1 mmol) and triethylamine (0.29 g, 2.4 mmol), and this was heated to reflux for 6 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a solution of the residue obtained in a solvent mixture of methanol/tetrahydrofuran=1:1 (50 mL) was added 10% palladium-carbon (50 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 3 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.36 g, 70% yield) as a pale yellow solid.