Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44]>CO.ClCCl>[OH:26][CH2:25][CH2:24][N:23]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]1[C:16]2[CH2:22][N:21]([C:43](=[O:44])[CH2:42][O:41][CH3:40])[CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)[N:14]=1
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COCC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (40 mg, 0.09 mmol, Example 1) was dissolved in methanol (0.5 mL) and dichloromethane (3 mL). Triethylamine (0.013 mL, 0.09 mmol) was added followed by methoxyacetyl chloride (8.55 μL, 0.09 mmol). The reaction mixture was stirred at room temperature for 2 h and the solvent was evaporated under reduced pressure. The crude was dissolved in few drops of dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxyethanone (8.4 mg, 16.96%). HPLC, ms detection: (ESI) (M+1) m/z 501;
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.C([Li])CCC.[CH3:19][S:20]SC.[OH-].[Na+]>O1CCCC1>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:20][CH3:19])[CH:3]=2)[CH:8]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CSSC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2cc(SC)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A solution of 2-bromo-6-methoxynaphthalene (22.2 g, 93.6 mmol) in tetrahydrofuran (500 ml) was cooled to -78° C. and n-butyllithium (75 ml 1.6 M in THF, 121.7 mmol) was added dropwise over 15 minutes. After 0.5 h, dimethyl disulfide (13 ml, 140 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 16 h, 1N sodium hydroxide (100 ml) was added and the reaction mixture was stirred for 1 h. The organic layer was separated and washed with 1N sodium hydroxide, 5% aqueous sodium sulfite, and brine, and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was recrystallized form ethyl acetate and hexane to give 11.1 g of 2-methoxy-6-methylthio-naphthalene as a solid (58% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCN1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of 4-bromobutanenitrile (1.50 g, 10.17 mmol) in dimethyl formamide (20 ml) were added 1-(4-chlorophenyl)piperazine (2.0 g, 10.17 mmol) and potassium carbonate (2.81 g, 20.34 mmol) at room temperature and the reaction mixture was stirred for 3 h at same temperature. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 ml) and the aqueous layer was extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over anhydrous sodium sulphate. The solvent in the organic layer was removed under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate in hexane to yield the title compound (2.32 g, 86% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:25](Cl)[C:26]([O:28]C)=[O:27].Cl>CN(C)C=O.O>[C:10]1([C:7]2[C:6]3[CH:16]=[C:2]4[O:1][CH:25]([C:26]([OH:28])=[O:27])[O:17][C:3]4=[CH:4][C:5]=3[O:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cc2onc(-c3ccccc3)c2cc1O
Reactant: COC(=O)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C1Oc2cc3onc(-c4ccccc4)c3cc2O1
Reaction time: 2.5 h
Yield: 55.3 %

Procedure:
A mixture of 5,6-dihydroxy-3-phenyl-1,2-benzisoxazole (2.9 g), potassium carbonate (10.7 g) and methyl dichloroacetate (3.7 g) in 50 ml of N,N-dimethylformamide was stirred at 90°-100° C. for 2.5 hours. After cooling, water (50 ml) was added to the mixture followed by stirring it at 90°-100° C. for 40 minutes. After cooling and acidifying the mixture with hydrochloric acid, the mixture was extracted with ether. The ether layer was washed with water, dried and evaporated to remove the solvent. The residue was washed with methylene chloride, recrystallized from acetone/water to give 2.0 g of 3-phenyl-1,3-dioxolo[4,5-f]-1,2-benzisoxazole-6-carboxylic acid. m.p.: 202.5°-203.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[F:31][C:32]([F:85])([F:84])[C:33]1[CH:34]=[C:35]([CH:77]=[C:78]([C:80]([F:83])([F:82])[F:81])[CH:79]=1)[C:36]([N:38]1[CH2:42][C@@:41]([CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][C:55]3([C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[CH2:59][C@@H:58]3[O:66][CH2:67][C:68]([N:70]([CH3:76])[CH2:71][CH2:72][CH2:73][NH:74][CH3:75])=[O:69])[CH2:54][CH2:53]2)([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[O:40][CH2:39]1)=[O:37]>C(Cl)Cl>[F:83][C:80]([F:81])([F:82])[C:78]1[CH:77]=[C:35]([CH:34]=[C:33]([C:32]([F:31])([F:85])[F:84])[CH:79]=1)[C:36]([N:38]1[CH2:42][C@@:41]([CH2:50][CH2:51][N:52]2[CH2:53][CH2:54][C:55]3([C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[CH2:59][C@@H:58]3[O:66][CH2:67][C:68]([N:70]([CH3:76])[CH2:71][CH2:72][CH2:73][N:74]([CH3:75])[C:14]([C:12]3[S:13][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:11]=3)=[O:16])=[O:69])[CH2:56][CH2:57]2)([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[O:40][CH2:39]1)=[O:37]
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)s1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCN(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)s1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
The compound (94 mg, 0.385 mmol) obtained in Example 4c was dissolved in methylene chloride (4 mL), triethylamine (80 μL, 0.578 mmol) and pivaloyl chloride (52 μL, 0.424 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. The compound (300 mg, 0.385 mmol) obtained in Example 1k was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:2→0:100, v/v) to give the title compound (366 mg; yield, 94%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:11][C:12]1[CH:13]=[C:14]([N:19]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>C1(C)C=CC=CC=1.C[Si](C)(C)O[Si](C)(C=C)C=C.C[Si](C)(C)O[Si](C)(C=C)C=C.C[Si](C)(C)O[Si](C)(C=C)C=C.[Pt].[Pt]>[CH3:27][C:22]1[CH:21]=[C:20]([N:19]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][CH2:33][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:34][CH:35]=2)[C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Agent: [Pt]
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1)(OCC)OCC
Temperature: 25 °C
Yield: 90.1 %

Procedure:
Into a three-necked flask, 40 ml of toluene, 6.0 g of triethoxysilane and 0.54 mmol of diplatinum (0) tris(tetramethyldivinyldisiloxane) in toluene were placed, and 20 ml of a toluene solution containing 9.9 g of 4-[N,N-bis(3,4-dimethylphenyl)amino]styrene was added dropwise with stirring at room temperature. After the addition was completed, the mixture was stirred at 70° C. for 3 hours, and thereafter the solvent was removed under reduced pressure to obtain oily pale yellow 4-[N,N-bis(3,4-dimethylphenyl)amino]-[2-(triethoxysilyl)ethyl]benzene in an amount of 13.4 g (yield: 90.1%).
Reaction SMILES: CCC1C=CC(=O)[C:5]2=C[C:7]3[CH2:25][N:24]4[C:10](=[CH:11][C:12]5[C@@](O)(CC)C(=O)OC[C:13]=5[C:22]4=O)[C:8]=3[NH:9][C:4]=12.[CH2:30]([Cl:32])Cl.CN(C)C=[O:36].N1C=CC=CC=1>C(N(CC)CC)C>[N:24]1([CH:25]2[CH2:5][CH2:4][N:9]([C:30]([Cl:32])=[O:36])[CH2:8][CH2:7]2)[CH2:22][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: ClCCl
Reactant: CCc1ccc(=O)c2cc3c([nH]c1-2)-c1cc2c(c(=O)n1C3)COC(=O)[C@]2(O)CC
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Cl)N1CCC(N2CCCCC2)CC1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
In a suitable vessel were charged 7-Ethyl-10-hydroxycamptothecin (1 g), methylene dichloride, dimethylformamide (0.186 gm) and pyridine (3 ml) under nitrogen atmosphere. A solution of [1,4′]bipiperidinyl-1′-carbonyl chloride (0.88 g), methylene dichloride and triethylamine (1 ml) was prepared and added to the above suspension and stirred at 30-40° C. for 2 hours. The solvent was distilled out under reduced pressure at 50° C. and hexane was added under stirring as an antisolvent to isolate crystalline compound, which was then filtered, washed with hexane and dried under reduced pressure at 50° C. The yield was 1.30 g (86.89%); HPLC purity—99.8%
Reaction SMILES: O=[O+][O-].[O:4]=O.[C:6]([O:10][C:11](=[O:26])[N:12]([CH2:16][C:17]1[CH:22]=[C:21]([CH:23]=C)[CH:20]=[CH:19][C:18]=1[Cl:25])[CH:13]1[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl.CO>[C:6]([O:10][C:11](=[O:26])[N:12]([CH2:16][C:17]1[CH:22]=[C:21]([CH:23]=[O:4])[CH:20]=[CH:19][C:18]=1[Cl:25])[CH:13]1[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=O
Reactant: C=Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc(C=O)ccc1Cl)C1CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A O3/O2-mixture (generated by a Fischer ozonolyser) was gently bubbled through a sol. of (2-chloro-5-vinyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (10.0 g, 32.5 mmol) in CH2Cl2 (356 mL) and MeOH (44 mL) at −78° C. for 60 min. The mixture turned light blue, and pure O2 was bubbled through the mixture until it became colourless. The mixture was purged with a stream of nitrogen for 60 min, and Me2S (44.0 mL) was added. The mixture was stirred at −78° C. for 2 h. The solvents were removed under reduced pressure, and the residue was dried under high vacuum overnight to yield to crude title compound (11.7 g, quantitative yield) that was used further without purification. LC-MS: tR=1.04 min; ES+: 295.34.
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11](=[O:15])[CH:12]([CH3:14])[CH3:13].N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([C@@H:2]([C@@H:11]([OH:15])[CH:12]([CH3:14])[CH3:13])[CH:1]=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CCCc1ccccc1
Reactant: CC(C)C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](O)[C@@H](C=O)Cc1ccccc1
Reaction time: 26 h
Yield: 75 %

Procedure:
A solution of freshly distilled hydrocinnamaldehyde (132 μL, 1.0 mmol) in 500 μL dimethylformamide was added slowly over the course of 24 h to a stirring suspension of isobutyraldehyde (272 μL, 3.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at room temperature. After 26 h, the resulting solution was diluted with ethyl acetate and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions dichloromethane. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated in vacuo. Flash chromatography (3:1 hexanes:ethyl acetate) afforded the title compound as a clear, colorless oil in 75% yield (155 mg, 0.75 mmol), 91% ee and 95:5 anti:syn. IR (film) 3466, 3086, 3063, 3028, 2962, 2932, 2834, 2733, 1950, 1875, 1806, 1722, 1604, 1496, 1454, 1390, 1368, 1244, 1180, 1136, 1049, 1031, 993.0, 964.3, 849.7, 800.6, 739.8, 700.2 cm−1; 1H NMR (300 MHz, CDCl3) δ9.83 (d, 1H, J=2.1 Hz, CHO); 7.27 (m, 5H, Ar—H); 3.43 (ddd, 1 H, J=6.6, 6.6, 4.5 Hz, CHOH); 3.06 (dd, 1H, J=13.2, 7.8 Hz, PhCH2); 2.92 (dd, 1H, J=13.2, 6.9 Hz, PhCH2); 2.81 (m, 1H, CHCH2); 2.15 (d, 1H, J=6.0 Hz, OH); 1.90 (m, 1H, CH(CH3)2); 0.96 (d, 3H, J=6.6 Hz, CH(CH3)2); 0.92 (d, 3H, J=7.2 Hz, CH(CH3)2); 13C NMR (75 MHz, CDCl3) δ205.6, 129.2, 128.9, 128.6, 126.8, 76.9, 55.8, 33.4, 32.0, 19.7, 18.2; HRMS (CI) exact mass calcd for [M+H]+ (C13H19O2) requires m/z 207.1385, found m/z 207.1386; [α]D=−7.9 (c=1.0, CHCl3). The product ratios were determined by HPLC analysis of the corresponding alcohol (obtained by NaBH4 reduction) using a Chiracel OJ and OJ guard column (1.0% ethanol/hexanes, 1 mL/min); (2S, 3S) anti isomer tr=7.5 min, (2R, 3R) anti isomer tr=9.4 min, (2R, 3S) and (2S, 3R) syn isomers tr=6.3, 6.9 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]1([C:41]2[CH:46]=[CH:45]C(O)=[CH:43][CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][C:24]2[CH:43]=[CH:42][C:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:46][CH:45]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccc(-c5ccccc5)cc4)cc3)c2cc1OC
Yield: 34.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-phenylphenol (44 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (29 mg, yield 32%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:10]([CH2:11][C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[O:13])[C:9]2[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:6](=[O:36])[CH2:5]1.Br[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[N:40]=1.O>CN(C=O)C>[C:51]([O:50][C:48]([N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([CH2:38][CH:5]2[C:4](=[O:3])[N:10]([CH2:11][C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[O:13])[C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[N:7]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:6]2=[O:36])=[N:40]1)=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: COc1ccccc1N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)C(C)C
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
45 mg of Sodium Hydride (60% in oil, 1.12 mmol) is added to a solution of 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(2-methoxy-phenyl) acetamide, prepared as in Part D, (430 mg. 0.934 mmol) in DMF (10 mL) and the resultant mixture stirred at RT for 0.5 h prior to the addition of 3-Bromomethyl-1-tert-butoxycarbonyl-1H-indazole (291 mg, 0.934 mmol) to the reaction mixture. After stirring 22 h at RT, water (10 mL) is added and the resultant mixture extracted into ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL), brine (10 mL), dried (MgSO4), and concentrated in vacuo to afford the crude product which is purified by silica gel flash column chromatography using 3% methanol in methylene chlorideas eluent to give the desired product (260 mg) as a beige solid, which exists as 3:2 mixture of rotamers (major rotamer recorded): 1H NMR (300 MHz, CDCl3) δ8.1 (t, 1H, J=8.0), 7.90 (m, 1H), 7.60-6.90 (m, 15H), 5.05 (m, 1H, J=6.9), 4.60-3.40 (m, 8H), 1.7 (s, 9H), 1.16 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH2:11]O)([CH3:10])[C:6]1=[O:13])=[O:4].S(Cl)([Cl:24])=O.CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH2:11][Cl:24])([CH3:10])[C:6]1=[O:13])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CCl)C1=O
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To 8.79 g of Compound 2-1 obtained in Production Example 1, 3.04 ml of thionyl chloride and 0.15 ml of DMF were added. The resulting mixture was stirred in an oil bath of 90° C. for 2.5 hours. After the reaction, water was added to the reaction solution thus obtained, and extraction with toluene was carried out. The organic layer thus extracted was washed with a saturated aqueous solution of sodium carbonate and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 6.57 g of Compound 3-1-3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14]C(N3CCCCC3)[CH2:12][CH2:11]2)=[CH:6][N:5]=1)([O-:3])=[O:2].[CH2:22]([N:26]1CCN(C2C=CC(N)=NC=2)CC1)[CH:23]([CH3:25])[CH3:24].CN1CCN(C2C=CC(N)=NC=2)CC1>>[CH2:22]([N:26]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CN1CCN(c2ccc(N)nc2)CC1
Reactant: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cn1
Agent: CN1CCN(c2ccc(N)nc2)CC1
Product: CC(C)CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1

Procedure:
1-isobutyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted 5-(4-isobutylpiperazin-1-yl)pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.88 (d, J=6.73 Hz, 6H) 1.71-1.84 (m, 1H) 2.10 (d, J=7.32 Hz, 2H) 2.46-2.58 (m, 4H) 2.97-3.07 (m, 4H) 4.12 (s, 2H) 6.45 (d, J=8.78 Hz, 1H) 7.14 (dd, J=8.78, 2.93 Hz, 1H) 7.75 (d, J=2.93 Hz, 1H). LCMS (ESI) 235 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:16]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:18])[CH3:17]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][CH2:21][CH2:20][O:19][CH:16]([CH3:18])[CH3:17])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)OCCCN
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Reaction time: 48 h

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (40 g) was dissolved in dichloromethane (1.4 L) and triethylamine (23.3 mL). 3-Isopropoxypropylamine (19.3 mL) was added dropwise. After 48 hours, the reaction mixture was washed successively with water and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. (7-Bromo-3-nitroquinolin-4-yl)-(3-isopropoxypropyl)amine was isolated as a tan solid (51.2 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11](=[O:19])[CH:12]=[C:13]([CH2:17]Cl)[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:20][C@H:21]([C:23]([NH:25][CH3:26])=[O:24])[CH3:22].Cl.C(N(C(C)C)CC)(C)C>CC#N>[CH2:2]([O:9][C:10]1[C:11](=[O:19])[CH:12]=[C:13]([CH2:17][NH:20][C@@H:21]([CH3:22])[C:23]([NH:25][CH3:26])=[O:24])[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1CCl
Reactant: CNC(=O)[C@H](C)N
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H](C)NCc1cc(=O)c(OCc2ccccc2)cn1C
Temperature: 85 °C
Yield: 87.1 %

Procedure:
A mixture of 5-(benzyloxy)-2-(chloromethyl)-1-methylpyridin-4(1H)-one hydrochloride (7.55 g, 25.0 mmol), H-Ala-NHMe.HCl (5.14 g, 37.0 mmol) and diisopropylethylamine (12.5 mL, 72.0 mmol) in CH3CN (50 mL) was heated at 85° C. under a nitrogen atmosphere for overnight. Volatiles were removed in vacuo, and the residue was pre-purified by column chromatography on silica gel using a mixture of MeOH and ethyl acetate as eluant (solvent gradient of 10, 15 and 20% MeOH in ethyl acetate). The fractions rich in product were combined and evaporated to dryness. Further purification by column chromatography on silica gel using a mixture of H2O and CH3CN (1-5% H2O content) and then a 10% MeOH in dichloromethane solution afforded (S)-2-((5-(benzyloxy)-1-methyl-4-oxo-1,4-dihydropyridin-2-yl)methylamino)-N-methylpropanamide (7.17 g) in 87% yield. MS m/z 352 [M+Na]+, 330 (100%) [M+1]+, 228, 138, 91.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br.Br[CH2:45][C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)=[O:47]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]([C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:47])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3cccnc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(pyridin-3-yl)ethanone hydrobromide and isolated as light-yellow solid. MS(m/e): 402.3 (MH+).