Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]([O:10]C)=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.[O:12]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C>C1COCC1>[CH:3]1([C:8](=[O:10])[CH2:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=2)=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CCCC1)c1ccc(Oc2ccccc2)cc1
Yield: 63.2 %

Procedure:
Sodium hydride (1.508 g, 37.7 mmol, 60% suspension in mineral oil) was added in small portions to a solution of methyl cyclopentanecarboxylate (1.449 g, 11.31 mmol) and 1-(4-phenoxyphenyl)ethanone (2.00 g, 9.42 mmol) in THF (100 mL). Ethanol (0.5 mL) was then added. The mixture was heated to reflux for 5.5 h, quenched with saturated NaCl (50 mL) and acidified to pH 2 with 1 N HCl. THF was evaporated in vacuo. The residue was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with 5% ethyl acetate in hexanes and eluting with 5-20% ethyl acetate in hexanes, gave 1-cycloperityl-3-(4-phenoxyphenyl)propane-1,3-dione as white solid (1.837 g, 63% yield). MS (ES+) m/z: 309 (M+H); LC retention time: 5.015 min (analytical HPLC Method A).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[NH:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N:4]1([CH2:3][CH2:2][N:21]=[S:19]([C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=2)([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:20])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: ClCCN1CCOCC1
Reactant: N=S(=O)(CCCCOCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(S(=O)(CCCCOCc2ccccc2)=NCCN2CCOCC2)cc1

Procedure:
Following the procedures used in Example 2, the title compound is prepared from 4-(2-chloroethyl)morpholine and S-(4-nitrophenyl)-S-[4-(phenylmethoxy)butyl]sulfoximine.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[CH3:12][C:13]1([CH3:25])[C:22]2[C:17](=[CH:18][C:19]([Br:23])=[CH:20][CH:21]=2)[C:16](=O)[CH2:15][CH2:14]1>C1COCC1.CCOCC.C(OC(=O)C)C>[CH3:1][C:2]1[S:3][C:4]([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:13]([CH3:25])([CH3:12])[CH2:14][CH:15]=2)=[CH:5][CH:6]=1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: Cc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 62.3 %

Procedure:
To a cold (−78° C.) solution of 2-methylthiophene (800 mg, 8.1 mmol) in THF (10 mL) was added n-BuLi (1.6M solution in hexane, 5 mL). The mixture was stirred for 1.5 hours and transferred to a cold (−78° C.) flask containing 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound A, 1.63 g, 6.5 mmol), in THF (15 mL). The mixture was gradually warmed to 0° C. The reaction mixture was diluted with ether:ethylacetate (1:1, 80 mL), washed with water (10 mL), brine (10 mL). dried with MgSO4 and the solvent was removed by evaporation. The crude material was dissolved in dichloroethane (20 mL) and pTSA (40 mg) was added. The mixture was stirred at ambient temperature for 16 hours and at 50° C. for 4 hours. . The reaction mixture was diluted with ether (150 mL), washed with aqueous 10% NaHCO3 (10 mL), brine (10 mL) and dried with MgSO4. Purification by chromatography on silica gel gave 1.35 g of the title compound as a white solid.
Reaction SMILES: FC(F)(F)C1C=CC2NC3C=CC=CC=3N=C(N3CCN[C@@H](CCOC)C3)C=2C=1.Cl.[CH3:31][C:32]1[S:41][C:40]2[NH:39][C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[N:36]=[C:35]([NH2:46])[C:34]=2[CH:33]=1.[CH3:47][O:48][CH2:49][C@H:50]1[CH2:55]N[CH2:53][CH2:52][NH:51]1>>[CH3:47][O:48][CH2:49][C@@H:50]1[NH:51][CH2:52][CH2:53][N:46]([C:35]2[C:34]3[CH:33]=[C:32]([CH3:31])[S:41][C:40]=3[NH:39][C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[N:36]=2)[CH2:55]1
Reactant: COC[C@H]1CNCCN1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Agent: Cl
Product: COC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Yield: 39.8 %

Procedure:
By using a similar coupling method to (S)-2-trifluoromethyl-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b, e][1,4]diazepine, using 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.9 g) and (R)-2-methoxymethyl-piperazine (2.6 g) affords the title compound as a yellow solid (974 mg, 41%); mp 87-95° C.: 1H NMR (CDCl3) δ 2.32 (d, 3H), 2.69 (dd, 1H), 3.10-2.87 (m, 4H), 3.33 (dd, 1H), 3.38 (s, 3H), 3.49-3.43 (m, 1H), 3.94 (d, 1H), 4.02 (d, 1H), 4.98 (s, 1H), 6.30 (s, 1H), 6.61 (dd, 1H), 6.88 (dt, 1H), 6.97 (dt, 1H), 7.03 (dd, 1H); MS (APCI) m/z (rel intensity) 343.3 (100).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1.Cl[CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([O:17][CH2:16][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1)=[O:23]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Sodium hydride (218 mg) was added to a solution of 1H-indole-3-carboxylic acid (400 mg) in N,N-dimethylformamide (4 ml) with ice cooling, and the mixture was stirred for 30 minutes. Chloromethyl2,2-dimethylpropionate (373 mg) was added thereto, and the mixture was warmed to room temperature and stirred for 2 hours. Water was added thereto, and the aqueous phase was washed with ether. The aqueous phase was acidified by 2 N hydrochloric acid and extracted with ether. The organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give the title compound (540 mg, Y.:79%) as orange crystals.
Reaction SMILES: C(OC(N1CCC(C(O[C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[C:44]([O:48][C:49]([N:51]1[CH2:57][CH2:56][CH2:55][CH:54]([CH:58]([OH:60])[CH3:59])[CH2:53][CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1.CCOC(C)=O>[C:44]([O:48][C:49]([N:51]1[CH2:57][CH2:56][CH2:55][CH:54]([CH:58]([O:60][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)[CH3:59])[CH2:53][CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45]
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(O)C1CCCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (267 mg, 0.82 mmol), 4-(1-hydroxyethyl)azepane-1-carboxylic acid tertbutyl ester (300 mg, 1.23 mmol) and triphenylphosphine (365 mg, 1.39 mmol) in dioxane (3 mL) was added dropwise DIAD (273 ul, 1.39 mmol) and the reaction mixture was stirred at RT for 2 h. The mixture was then diluted with EtOAc and washed with aq. NaOH (1N). The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were then washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM followed by Si-PCC, gradient 0-10% MeOH in EtOAc) affording the title compound as a colorless oil (60 mg, 15%). LCMS: RT 4.08 min [M+H]+ 551.2
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>CCCCCC>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: COc1cc(S(N)(=O)=O)cc(C(=O)Cl)c1OC
Yield: 94.7 %

Procedure:
419 g (1.6 mole) of 2,3-dimethoxy-5-sulphamoyl benzoic acid and 1,351 g (11.35 moles) of thionyl chloride are placed in a 2 liter flask fitted with an agitator, a thermometer and a condenser connected to a soda bubbler. The mixture is brought to reflux for 1 hour, after which the excess thionyl chloride is expelled under vacuum. The residue is dissolved in 1,000 ml of hexane, filtered, washed twice with 500 ml of petroleum ether and dried in a desiccator under vacuum. 424 g (yield 94.8%) of 2,3-dimethoxy-5-sulphamoyl benzoyl chloride is obtained with a melting point of 153° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:22]#[N:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>CCO.CCOC(C)=O.CO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:22]#[N:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Reaction time: 19 h

Procedure:
To a solution of 3-(3-cyano-1H-Indol-5-yl)-3-phenyl-acrylic acid ethyl ester LXIII (1.81 g, 5.71 mmol) in EtOH/EtOAc/MeOH (1/1/1, 60 ml) was added a catalytic amount of Pd/C (5%). The mixture was hydrogenated in a Parr apparatus at 60 psi of H2 for 19 hours, filtered through celite, and the filter cake was washed with MeOH and EtOAc. The filtrate was concentrated to afford 3-(3-Cyano-1H-Indol-5-yl)-3-phenyl-propionic acid ethyl ester LXIV as a white foamy solid in quantitative yield (1.86 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.[CH2:12]([C:19]1([N:26]([CH3:28])[CH3:27])[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:12]([C:19]1([N:26]([CH3:27])[CH3:28])[CH2:24][CH2:23][CH:22]([NH:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1c[nH]c2ccccc12
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CN(C)C1(Cc2ccccc2)CCC(NCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.5 %

Procedure:
292 mg C-(1H-Indol-3-yl)-methylamine were partly dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 463 mg 4-benzyl-4-dimethylamino-cyclohexanone (see example 3), glacial acetic acid (4 mmol) and sodium triacetoxyborohydride (550 mg), the suspension was stirred for 72 hours at room temperature. For working up, water (10 ml) was added to the reaction mixture. The organic phase was separated off and the aqueous phase was extracted twice with ether and then rendered strongly alkaline with sodium hydroxide solution. It was extracted again with ethyl acetate (4×10 ml). A pale precipitate precipitated out of the combined ethyl acetate phases even during the processing. After cooling, this was filtered off with suction, washed twice with cold ethyl acetate and dried. 235 mg 1-benzyl-N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-cyclohexane-1,4-diamine were obtained as a cis/trans mixture (m.p. 194-198° C.).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16](O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[CH2:66]([O:69][C:70]([C:72]1([NH2:75])[CH2:74][CH2:73]1)=[O:71])[CH:67]=[CH2:68]>C1COCC1>[CH2:66]([O:69][C:70]([C:72]1([NH:75][C:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)([CH3:29])[C:9](=[O:28])[N:10]([C:19]4[CH:20]=[C:21]([Cl:27])[C:22]([F:26])=[C:23]([Cl:25])[CH:24]=4)[C:11]3=[N:15][CH:14]=2)=[O:17])[CH2:74][CH2:73]1)=[O:71])[CH:67]=[CH2:68]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
Reactant: C=CCOC(=O)C1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)c(F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (10 g, 22 mmol), was added to a 500 mL round bottomed flask containing THF (100 mL). To this solution was added HATU (9.1 g, 24 mmol), diisopropylethylamine (11 mL, 65 mmol) and 1-amino-cyclopropane-carboxylic acid allyl ester hydrochloride (4.3 g, 24 mmol). The reaction was allowed to stir at room temperature for 18 h. The organics were washed with water (2×30 mL) and brine (1×30 mL) then dried (MgSO4) and concentrated to afford crude 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazol[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (12.6 g, 22 mmol) which was taken onward without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][CH3:8])[NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=O>C(O)(=O)C>[CH2:7]([C:5]1[N:6]=[C:2]2[N:1]=[CH:11][CH:12]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:3]2[N:4]=1)[CH3:8]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: CCc1nc(N)n[nH]1
Solvent: CC(=O)O
Product: CCc1nc2nccc(-c3cccnc3)n2n1
Yield: 67.1 %

Procedure:
A mixture of 1.12 g of 3-amino-5-ethyl-1,2,4-triazole and 1.76 g of 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one in 25 ml of glacial acetic acid was refluxed for six hours and the procedure of Example 1 was continued to give 1.51 g of the desired product as colorless needles, mp 147°-149° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:47])=[C:8]([N:10]2[CH2:46][CH2:45][C:13]3[N:14]=[C:15]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[C:27]([CH3:44])=[CH:28][N:29]5[S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:36])=[O:35])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[CH3:48][S:49](Cl)(=[O:51])=[O:50].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:47])=[C:8]([N:10]2[CH2:46][CH2:45][C:13]3[N:14]=[C:15]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[C:27]([CH3:44])=[CH:28][N:29]5[S:34]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=4)(=[O:35])=[O:36])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([S:49]([CH3:48])(=[O:51])=[O:50])[C@H:20]([CH3:24])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN[C@H](C)C6)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(S(C)(=O)=O)[C@H](C)C6)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (52 mg, 0.080 mmol), prepared in a manner similar to that described in Example 25, methanesulfonyl chloride (0.01 mL, 0.096 mmol) and DIEA (0.042 mL, 0.240 mmol) in DCM (3 mL) was stirred at rt for 30 min. The reaction mixture was diluted with EtOAc, washed successively with sat NaHCO3, and brine, dried over Na2SO4 and concentrated. The resulting residue was purified via FCC (5-50% EtOAc/heptane) to provide (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 727.4 (M+H)+. To a solution of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (40 mg, 0.055 mmol) in MeOH (4 mL), NH4OH (0.325 mL, 8.25 mmol) and KOH (27.8 mg, 0.495 mmol) was added. The mixture was heated in a microwave reactor 100° C. for 1 h. The mixture was then filtered and concentrated. The resulting residue was purified via FCC (0-45% EtOAc/heptane) to provide (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1H-indol-4-yl)-4-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (d, J=2.02 Hz, 1 H) 7.40-7.43 (m, 1 H) 7.24 (dd, J=7.33, 1.01 Hz, 1 H) 7.09-7.16 (m, 3 H) 7.02 (d, J=1.26 Hz, 1 H) 6.87 (dd, J=7.83, 1.26 Hz, 1 H) 4.03-4.16 (m, 3 H) 3.70-3.84 (m, 2 H) 3.56 (d, J=12.88 Hz, 1 H) 3.33-3.42 (m, 2 H) 3.23-3.28 (m, 1 H) 3.14 (dd, J=12.88, 3.54 Hz, 1 H) 2.92-3.06 (m, 6 H) 2.79-2.90 (m, 1H) 2.22 (s, 3 H) 2.03 (s, 3 H) 1.32 (d, J=6.82 Hz, 3 H) 1.19 (dd, J=6.95, 1.89 Hz, 6 H); MS (ESI+) m/z 573.4 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[F:19].C([O-])=[O:21].[Na+].C(O)C>O>[F:19][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=2[C:15]([F:18])([F:17])[F:16])[C:3]=1[CH2:2][OH:21]
Reactant: COc1ccc2c(CBr)c(F)ccc2c1C(F)(F)F
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(CO)c(F)ccc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 1-bromomethyl-2-fluoro-6-methoxy-5-(trifluoromethyl)naphthalene (11.16 g, 35 mmol), sodium formate (5.85 g, 86 mmol), ethanol (134 mL) and water (34 mL) was heated to reflux with stirring. Dissolution occurred with 20 minutes. After 1.5 hours the heating source was removed, 2.5N NaOH (14mL) was added, and the reaction mixture was cooled to room temperature. The ethanol was removed, water (100 mL) was added and the solid was filtered. The white solid was washed with water and dried in vacuo to give the product in quantitative yield. A small portion was recrystallized from petroleum ether:ethyl acetate, m.p. 113°-114° C.
Reaction SMILES: C1(C=[CH:7][C:5]([OH:6])=CC=1)O.[C:9]([O-:13])(=[O:12])[CH:10]=[CH2:11].CC(C(OCCO)=O)=C.[N-:23]=[C:24]=[O:25]>[Sn].C(O)CCC>[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[NH2:23][C:24]([O:6][CH2:5][CH3:7])=[O:25]
Reactant: Oc1ccc(O)cc1
Reactant: [N-]=C=O
Reactant: C=CC(=O)[O-]
Agent: C=C(C)C(=O)OCCO
Agent: [Sn]
Solvent: CCCCO
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
First 700 parts of 535 molecule weight, polyhexyl orthophthalate were added to a glass resin kettle. A heating mantel was used to supply heat. The pot was also fitted with a thermometer and motorized stirrer. While stirring, the polyol was heated to 162° F. (72° C.) to degass at which temperature, 570 parts of isophorone diisocyanate (IPDI) were added. The temperature dropped to 130° F. (54° C.), but after 10 minutes began to rise again. Ten minutes later the material had exothermed to a peak temperature of 260° F. (127° C.) The prepolymer was allowed to react fully for 45 minutes with continuous stirring without heating. Two parts of hydroquinone were added next to stabilize the acrylate to be added in the subsequent phase of the reaction. The prepolymer was cooled further to 160° F. (71° C.) at which temperature, 367 parts of HEMA were added to completely react with the theoretical amount of free isocyanate available from the prepolymer. The temperature dropped to 150° F. (66° C.). A tin catalyst (T832) was added to the stirred material in the amount of 64 drops, the material exothermed to a peak temperature of 184° F. (84° C.) in 5 minutes. The material was then cooled to room temperature. After the acrylated urethane was allowed to sit at room temperature for 18 hours, an analysis for any residual amount of isocyanate was made. The % free NCO was 0.11. Four grams of butanol (a slight excess) were added to the reheated material to quench the remaining NCO groups. The viscous liquid was then poured into two glass quart jars which were then sealed.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17](=[S:19])[NH2:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C>CN(C)C=O.O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]1[S:19][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=S
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(CN2C(=O)CC[C@@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C

Procedure:
To a solution of the compound 68 (4.50 g) in dimethylformamide (15.0 mL) was ethyl bromopyruvate (2.33 mL) at 0° C. and the solution was stirred at room temperature for 2 Hours. To the reaction solution were added imidazole (4.08 g) and tert-butyldimethylsilyl chloride (4.52 g) at 0° C. and the solution was stirred at room temperature for 2 Hours. To the reaction solution were added ethyl acetate and water and then the solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with an aqueous saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:2→2:3) to give the title compound (4.75 g) having the following physical data.
Reaction SMILES: [CH3:1][O-:2].[Na+].[N:4]([C:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)([CH3:9])[CH3:8])=[N+:5]=[N-:6].Cl[C:25]1[C:30]([CH:31]=O)=[C:29]([NH:33]C(=O)OC(C)(C)C)[CH:28]=[CH:27][N:26]=1.Cl>CO.CCOC(C)=O>[N:4]([C:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[CH:31][C:30]3[C:29](=[CH:28][CH:27]=[N:26][C:25]=3[O:2][CH3:1])[N:33]=2)=[CH:12][CH:11]=1)([CH3:9])[CH3:8])=[N+:5]=[N-:6]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Reactant: CC(C)(N=[N+]=[N-])c1ccc(C(=O)Cc2cccs2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1nccc2nc(-c3ccc(C(C)(C)N=[N+]=[N-])cc3)c(-c3cccs3)cc12
Temperature: 65 °C

Procedure:
Sodium methoxide (25 weight % in methanol, 0.23 mL) was added to a stirred mixture of 1-[4-(1-azido-1-methylethyl)phenyl]-2-(2-thienyl)ethanone (2-4, 95mg, 0.33mmol) and tert-butyl(2-chloro-3-formylpyridin-4-yl)carbamate (1-3, 100 mg, 0.39 mmol) in methanol (2 mL), then heated to 65° C. for 2 h. The mixture was cooled to rt, diluted with EtOAc, and acidified with 1N HCl. The aqueous was extracted with ethyl acetate and the combined organics were washed with 1:1 brine:water, dried over magnesium sulfate, filtered, and concentrated to give a dark semi-solid. The crude product was purified via automated silica gel chromatography (0-45% EtOAc in hexane with 5% CH2Cl2 over 30 min) to give the title compound as an amber oil. LRMS m/z (M+1) Calcd: 402.2,. Found 402.2.