Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:31]=[CH:30][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:10]=3[OH:29])[N:8]=[C:4]2[CH:3]=1.[OH-].[K+].[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN1CCCC1=O>[C:34]1([S:40][C:2]2[CH:31]=[CH:30][C:5]3=[N:6][N:7]([C:9]4[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:10]=4[OH:29])[N:8]=[C:4]3[CH:3]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)CC(C)(C)c1cc(-c2ccccc2)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)(C)CC(C)(C)c1cc(-c2ccccc2)c(O)c(-n2nc3ccc(Sc4ccccc4)cc3n2)c1

Procedure:
The title compound is prepared according to the procedure of Example 4 from 20 g of the compound of Example 8, 20.4 g of 45% aqueous potassium hydroxide, 10.3 g of thiophenol and 100 g of N-methylpyrrolidone. The title compound is an oil purified by chromatography on silica gel using toluene as eluent.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([N+:19]([O-])=O)=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].O1CCCC1>[C].[Pd].CO>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([NH2:19])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc([N+](=O)[O-])cc3c2n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2n1

Procedure:
1.5 g of 8-nitro-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 10) is hydrogenated in 90 ml of a mixture of equal parts of tetrahydrofuran and methanol at normal temperature under a hydrogen pressure of 70 bar, with the addition of 0.21 g of 10% palladiumcarbon. The solution, freed of catalyst, is evaporated, the residue is taken up in ethyl acetate and a small amount of ethanol, filtered, and evaporated to 3/4 its quantity, thus precipitating 0.400 g of 8-amino-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 256°-258° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[CH:23]([C:25]1[C:33]2[C:29](=[CH:30][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:32]=2)[CH:28]=[C:27]([C:42]([F:45])([F:44])[F:43])[CH:26]=1)[CH3:24].[H-].[Na+]>CN(C)C=O>[C:16]1([C:3]2([CH2:2][O:1][CH:23]([C:25]3[C:33]4[C:29](=[CH:30][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[N:32]=4)[CH:28]=[C:27]([C:42]([F:45])([F:44])[F:43])[CH:26]=3)[CH3:24])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(Br)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (193 mg, 0.66 mmol) and 7-(1-bromoethyl)-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (280 mg, 0.66 mmol) in dimethylformamide (2.5 mL) at 0° C. was added sodium hydride (60% in mineral oil, 34.4 mg, 0.86 mmol). The resulting solution was stirred at 0° C. for 30 min. The reaction was quenched by the cautious addition of saturated ammonium chloride and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→20% EtOAc/Hex) gave 62 mg (15%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 8.24 (s, 1H), 7.94 (s, 1H), 7.32-7.45 (m, 4H), 7.23-7.29 (m, 2H), 5.75 (m, 2H), 5.04 (q, J=6.4 Hz, 1H), 3.81 (m, 2H), 3.67 (m, 2H), 3.44 (qAB, JAB=9.2 Hz, 2H), 3.10 (m, 2H), 2.23 (m, 2H), 2.03 (m, 2H), 1.52 (d, J=6.4 Hz, 3H), 1.48 (s, 9H), 0.97 (m, 2H), 0.00 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.2, 147.4, 142.9, 135.5, 128.5, 127.3, 126.4, 124.8 (q, J=272 Hz), 124.7 (q, J=32 Hz), 124.6, 121.1, 117.9 (q, J=4.8 Hz), 117.3 (q, J=2.9 Hz), 82.0, 79.3, 78.2, 74.1, 67.8, 41.8, 40.3 (br), 31.8, 28.6, 22.8, 17.9, −1.4. Mass spec.: 634.17 (MH)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:1]1([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 83 %

Procedure:
A solution of phenyl acetic acid (27.2 g.), benzyl alcohol (21.6 g.) and p-toluenesulfonic acid (380 mg.) in 100 ml. of toluene was heated under reflux under a Dean-Stark trap until the theoretical (3.6 ml.) quantity of water had been collected. On cooling, the solution was washed with dilute NaHCO3 and saturated NaCl and solvent was removed in vacuo. The resulting oil was distilled at 125°-129° (0.4 torr)1 to give pure benzyl phenylacetate, 37.7 g. (83% yield). ##STR229##
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[CH:3]=1.[CH2:10](I)[CH3:11]>C(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCI
Reactant: Oc1cc(Br)c(F)cn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCOc1cc(Br)c(F)cn1

Procedure:
Educt: 4-bromo-5-fluoro-pyridin-2-ol/ethyl iodide using silver carbonate in methylene chloride as a base
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:12])[NH:9][CH:10](O)[C:6]=2[C:5]([F:13])=[C:4]([F:14])[N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>CC(OC)(C)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:12])[NH:9][CH2:10][C:6]=2[C:5]([F:13])=[C:4]([F:14])[N:3]=1
Reactant: O=C1NC(O)c2c(F)c(F)nc(Cl)c21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: O=C1NCc2c(F)c(F)nc(Cl)c21
Temperature: 60 °C
Yield: 82 %

Procedure:
To an inert 50 mL round bottom flask with magnetic stirring was added 4-chloro-6,7-difluoro-1-hydroxy-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (4.39 g, 19.90 mmol) and trifluoroacetic acid (18.40 mL, 239 mmol). The solids were suspended with stirring and triethylsilane (7.95 mL, 49.8 mmol) was added. The reaction mixture was heated to 60° C. and stirred for 30 minutes at that temperature. The reaction mixture was subsequently cooled to room temperature and added dropwise to MTBE (88 mL) to produce a white precipitate. The suspension was cooled to 5° C. for 45 minutes. The solids were filtered, washed with MTBE (20 mL) and air dried on the filter to afford the title compound (3.336 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.58 (s, 2H), 9.13 (s br, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:3]=1.[C:22]([C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])([OH:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][NH:11][C:4]1[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=[C:2]([C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])[CH:33]=[CH:32][CH:31]=2)[CH:3]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COCc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COCc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
Argon is bubbled through a mixture of (6-chloro-2-methoxymethyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (200 mg, 0.58 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [266 mg, 1.28 mmol, see Example 49(b) step 2], Cs2CO3 (1.56 g, 2.52 mmol), and tetrakis(triphenylphosphine)palladium (0) (69 mg, 0.06 mmol) in ethylene glycol dimethyl ether (4 mL) and water (1 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 16 hours the mixture is diluted with water (40 mL) and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with 40% ethyl acetate:heptane to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxymethyl-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [165 mg, 60%, Example 85] as a solid. LCMS RT=2.59 minutes, MS: 474 (M+H). IC50=2.7 nM
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([OH:27])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:3]=12.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a suspension of 2-(4-chloro-3-(4-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (150 mg, 0.39 mmol) in CH2Cl2 (3 mL) were added morpholine (34 mg, 0.39 mmol), diisopropylethylamine (DIPEA) (200 μL, 1.2 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (180 mg, 0.47 mmol). The solution obtained was stirred at room temperature for 75 min before being purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane) followed by preparative HPLC yielding Compound 75 as a clear glass solid (11.5 mg).
Reaction SMILES: [NH:1]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:69][CH2:68][CH2:67][C@H:31]1[C:32]([NH:34][C@H:35]([C:37]([NH:39][C@H:40]([C:57]([O:59]CC1C=CC=CC=1)=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][CH2:49][C:50]1[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=1[Cl:52])=[O:47])=[O:38])[CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16][S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:70]([O:72][C:73]([CH3:74])([CH3:76])[CH3:75])=[O:71])[C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:69][CH2:68][CH2:67][C@H:31]1[C:32]([NH:34][C@H:35]([C:37]([NH:39][C@H:40]([C:57]([OH:59])=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][CH2:49][C:50]1[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=1[Cl:52])=[O:47])=[O:38])[CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16][S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 108.7 %

Procedure:
At 0° C. to the solution of 300 mg (0.210 mmol) of Boc-Asn-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 17) in 8 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Asn-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 17). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 230 mg (83%) of the title compound as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1>N1C=CC=CC=1>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1ccc(-c2cc(Cl)c3cc(F)ccc3n2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2cc(N3CCC(C(N)=O)CC3)c3cc(F)ccc3n2)cc1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4-Chloro-6-fluoro-2-(4-methylphenyl)quinoline and isonipecotamide as starting materials. It was obtained as white needles, mp 246°-249° dec on recrystallization from pyridine.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:20][C:21]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24]>C(Cl)Cl.CN1CCOCC1.ClC(OCC(C)C)=O>[C:11]1([CH2:10][C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:17]2[O:19][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:31])([F:32])[F:33])[C:21]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Yield: 44.5 %

Procedure:
Using the procedure of Step A of Example 7, a solution of 19.9 g of BOC-L-phenylalanine in 150 ml of methylene chloride and 20.6 ml of N-methyl-morpholine, 19.5 ml of isobutyl chloroformate in 75 ml of methylene chloride and 15.4 g of 2-amino-3-trifluoromethyl benzoic acid in 150 ml of methylene chloride and 8.3 ml of N-methyl-morpholine were reacted to obtain 14.5 g of 1,1-dimethylethyl N-[(S) 2-phenyl-1-[4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl]-ethyl]-carbamate melting at 145° C. and having a specific rotation of [α]D =-33.5°±2° (c=0.5% in CH3COOH).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([CH3:3])=[CH2:2]>CO.[Pd]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1ccc(OCOC)c(OC)c1
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc(C(C)C)cc1OC
Reaction time: 16 h

Procedure:
To a solution of 4-isopropenyl-2-methoxy-1-methoxymethoxy-benzene (3.5 g, 16.81 mmol) in 20 mL MeOH, Pd/C (10%, 350 mg) was added and the mixture was stirred 16 h under a H2 atmosphere. The reaction mixture was then filtered through Celite and evaporated in vacuo and briefly dried under vacuum to yield the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH:19]=[C:18]([C:20](OCC)=[O:21])[C:17]([C:25]([F:28])([F:27])[F:26])=[N:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[BH4-].[Na+]>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH:19]=[C:18]([CH2:20][OH:21])[C:17]([C:25]([F:28])([F:27])[F:26])=[N:16]3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(C2CCN(c3ncc(CC)cn3)CC2)nc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CCc1cnc(N2CCC(n3cc(CO)c(C(F)(F)F)n3)CC2)nc1

Procedure:
The compound was synthesized using ethyl 1-(1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate and sodium borohydride in a manner similar to that described in Journal of Medicinal Chemistry, 1996, 29, 341.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[H-].[Na+].[CH3:17][C:18]#[N:19].Cl>C1(C)C=CC=CC=1>[CH:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3](=[O:14])[CH2:17][C:18]#[N:19])=[CH:9][CH:8]=1)([CH3:12])[CH3:13]
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC(C)C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(C(=O)CC#N)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-Isopropoxy-benzoic acid methyl ester (2.2 g, 11.2 mmol, 1.0 eq) in dry toluene (15 mL) under N2, NaH (50-60% dispersion in mineral oil, 1.1 g, 22.4 mmol, 2.0 eq) was added. The mixture was heated at 80° C. and then dry CH3CN was added dropwise (2.8 mL, 56.0 mmol, 5.0 eq). The reaction was heated for 18 hours, then was allowed to cool down to room temperature and acidified with HCl 2N. The organic phase was recovered and 2.0 g of crude were obtained and it was used for cyclization without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1.[Cl:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: CN1Cc2cncn2-c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(Cl)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5 g (23.5 mmol) of 4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 30 ml of dimethylformamide are treated with 3.20 g (23.5 mmol) of N-chlorosuccinimide and stirred at room temperature for 1.5 hours and at 60° for 10 minutes. The clear brown solution is poured into about 200 ml of water and extracted three times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on a silica gel column and subsequent recrystallization from ethyl acetate there is obtained 3-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 193°-194°.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C([O:6][C:7](=O)[NH:8][C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[CH:10][C:11]#[N:12])C.[CH3:22][CH:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]([NH:33][NH2:34])=O)[CH2:27][CH2:26]1)[CH3:24].O>CN1CCCC1=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:9]1[NH:8][C:7](=[O:6])[N:34]2[N:33]=[C:31]([CH:28]3[CH2:29][CH2:30][N:25]([CH:23]([CH3:24])[CH3:22])[CH2:26][CH2:27]3)[N:12]=[C:11]2[CH:10]=1
Reactant: CC(C)N1CCC(C(=O)NN)CC1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
In a round-bottom flask fitted with reflux condenser and a drying tube filled with calcium chloride, 500 mg (1.70 mmol) of ethyl[2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate and 310 mg (1.70 mmol) of 1-(1-methylethyl)piperidin-4-carbohydrazide (Example 38A) were dissolved in 2 ml of 1-methyl-2-pyrrolidone, and the reaction mixture was stirred at 160° C. for 3 h. The reaction solution was cooled to 100° C., water (20 ml) was added and the mixture was then cooled to RT and stirred for 15 min. The reaction mixture was extracted with dichloromethane (3×50 ml), and the combined organic phases were dried over magnesium sulfate and concentrated. The crude product was chromatographed on basic aluminum oxide (mobile phase dichloromethane/methanol 10:1, then dichloromethane/methanol/17% strength aqueous ammonia solution 15:2:0.2). This gave 2.55 g (78% of theory) of the product.
Reaction SMILES: [Cl:1][SiH:2]([CH2:4][SiH](Cl)Cl)[Cl:3].[CH2:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[CH2:10]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:12][Si:11]([CH3:14])([CH3:13])[CH2:8][CH2:9][CH2:10][Si:2]([CH3:4])([Cl:3])[Cl:1]
Reactant: C=CC[Si](C)(C)C
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C[Si](C)(C)CCC[Si](C)(Cl)Cl
Yield: 145 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 9.3 g (0.04 mole) of bisdichlorosilylmethane, 13.7 g (0.12 mole) of allyltrimethylsilane, and 80 μl of 1% chloroplatinic acid solution in isopropanol were placed and reacted for 2 hours at reflux under the dry nitrogen atmosphere. Vacuum distillation gave 13.3 g (134°-136° C./0.05 mmHg) of [{3-(trimethylsilyl)propyl}dichlorosilyl]methane in 75.1% yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[C:3]([O:5][CH:6]([O:10][C:11]([O:13]C1C=CC(S(C)(=O)=O)=CC=1)=[O:12])[CH:7]([CH3:9])[CH3:8])=[O:4].O[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32]>ClCCl>[CH3:24][CH:2]([CH3:1])[C:3]([O:5][CH:6]([O:10][C:11]([O:13][N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32])=[O:12])[CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)C(=O)OC(OC(=O)Oc1ccc(S(C)(=O)=O)cc1)C(C)C
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(C)C(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C

Procedure:
2-Methyl-1-[4-(methylsulfonyl)phenoxycarbonyloxy]propyl 2-methylpropanoate D6 is dissolved in dichloromethane at a concentration of 10% (w/vol). N-hydroxysuccinimide (1.1 equivalents) is added to the solution. The reaction mixture is warmed to reflux and stirred until the reaction is complete. The organic phase is extracted twice with a 10% potassium carbonate solution followed by a wash with water (2×). Drying over sodium sulfate is followed by solvent evaporation to provide the title compound E2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH3:15]O>>[CH3:15][O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH2:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: CO
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1
Product: COC(=O)c1ccc2cc(N)ccc2c1

Procedure:
6-Amino-naphthalene-2-carboxylic acid (561 mg, 3 mmol) was esterified with MeOH using Method B to give the title compound.
Reaction SMILES: C[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)(C)C.C(C1C=CC(CCl)=CC=1)=C.[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1N1CCNCC1.CO>[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:2][N:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)=[CH:27][CH2:28]2)=[CH:10][CH:9]=1)=[CH2:12]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: C=Cc1ccc(C(C)(C)C)cc1
Agent: C=Cc1ccc(CCl)cc1
Agent: Cl
Agent: c1ccc(N2CCNCC2)nc1
Solvent: CO
Product: C=Cc1ccc(CN2C=CC(N3CCNCC3)=CC2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Dye-labeled poly(4-tert-butylstyrene)-supported pyridylpiperazine catalyst for the acylation of phenols. 4-Vinylbenzylchloride was passed through neutral alumina to remove any inhibitors. 1-(4-Vinylbenzyl)-4-pyridylpiperazine was prepared by dissolving 4.32 mL of 4-vinylbenzylchloride and 10 g of N-(4-pyridyl)piperazine in 100 mL of methanol. The solution was allowed to reflux overnight. After cooling to room temperature, 20 mL of 6 N HCl was added and the solution was extracted three times with ether. The ether extracts were discarded and 20 g of NaOH in 20 mL of water was added dropwise to the aqueous solution. The resulting precipitate was recovered by filtration and purified by column chromatography using 5% triethylamine in ethyl acetate as the eluent. Removal of the solvent under reduced pressure produced the product in 72.1% yield. 1H NMR: δ 8.2 (d, 6.6 Hz, 2H), 7.3 (dd, J=6.4, 6.6 Hz, 4H), 6.7 (dd, J=10.7, 17.6 Hz, 1H), 6.6 (d, 6.4 Hz, 2H), 5.7 (d, 17.6 Hz, 1H), 5.2 (d, 10.7 Hz, 1H), 3.5 (s, 1H), 3.3 (t, 5.2 Hz, 4H), 2.5 (t, 5.1 Hz, 4H). 13C NMR: δ 155.2, 150.4, 137.6, 136.9, 136.7, 130.0, 126.4, 113.9, 108.5, 62.9, 52.7, 46.1.