Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:42])([CH3:41])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:40])([C@@:17]4([CH3:39])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2(C(O)=O)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C([N:45]([CH2:48]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:57])C=CC=CC=1>O1CCOCC1.CCOC(C)=O>[N:45]([C@:20]12[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]1[C@@H:22]1[C@@:17]([CH3:39])([CH2:18][CH2:19]2)[C@@:16]2([CH3:40])[C@@H:25]([C@:26]3([CH3:29])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:41])([CH3:42])[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:28][CH2:27]3)[CH2:24][CH2:23]1)=[C:48]=[O:57]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
To a slurry of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-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]chrysene-3a-carboxylic acid (10 g, 17.46 mmol) in 1,4-dioxane (200 mL) was added triethylamine (4.38 mL, 31.4 mmol) followed by diphenyl phosphoryl azide (5.82 mL, 26.2 mmol). The resulting white slurry was heated to 100° C. After 5 h, the reaction was allowed to cool to rt and was then diluted with EtOAc and washed with 1N NaOH (2×70 mL). The combined aqueous layer was extracted with EtOAc (2×150 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to slurry (about 75 mL) which was stored in a refrigerator overnight. The slurry was filtered and the white solid product was washed with Et2O. The liquid filtrate was concentrated to yellow slurry which was filtered and washed with Et2O to give more white solid product. The two batches of white solid were combined and dried under reduced pressure to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-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)benzoate (8.6 g, 86% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.0 (2H, d, J=8.2 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3 (1H, d, J=4.6 Hz), 4.8 (1H, s), 4.7 (1H, s), 3.9 (3H, s), 2.6 (1H, td, J=10.8, 5.8 Hz), 2.1-2.2 (2H, m), 1.8-2.0 (4H, m), 1.7-1.8 (1H, m), 1.7 (3H, s), 1.5-1.7 (5H, m), 1.4-1.5 (5H, m), 1.3-1.4 (2H, m), 1.2-1.3 (2H, m), 1.1 (3H, s), 1.1-1.1 (1H, m), 1.0 (3H, s), 1.0 (3H, s), 1.0 (3H, br. s.), 1.0 (3H, br. s.). 13C NMR (CHLOROFORM-d) δ ppm 14.2, 15.4, 16.2, 19.2, 19.5, 20.8, 21.0, 24.7, 27.4, 29.0, 29.2, 33.3, 36.0, 37.2, 39.0, 39.0, 40.3, 41.5, 41.8, 47.8, 49.0, 49.2, 51.7, 52.6, 66.8, 71.3, 110.2, 121.3, 123.7, 127.6, 128.2, 129.8, 146.0, 148.4, 148.6, 166.9.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([S:16]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2Br)[C:22]([O:24][CH3:25])=[O:23])(=[O:18])=[O:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH2:32].CCOC(C)=O.O>C1(C)C=CC=CC=1.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>[CH2:32]([C:28]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[S:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1)(=[O:18])=[O:17])[CH:31]=[CH2:30]
Reactant: COC(=O)c1ccc(Br)c(S(=O)(=O)N2CCCC(OCc3ccccc3)CC2)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCc1ccc(C(=O)OC)cc1S(=O)(=O)N1CCCC(OCc2ccccc2)CC1
Temperature: 110 °C
Yield: 52.8 %

Procedure:
Methyl 3-(4-benzyloxyazepan-1-yl)sulfonyl-4-bromo-benzoate (1.30 g, 2.69 mmol, 1.00 Eq), allyl(tributyl)stannane (1.07 g, 3.23 mmol, 1.20 Eq) LiCl (136.83 mg, 3.23 mmol, 1.20 Eq) and Pd(PPh3)4 (310.85 mg, 269.00 umol, 0.10 Eq) in TOLUENE (20 mL) was de-gassed and then heated to 110° C. for 16 hr under N2. TLC (PE:EtOAc=1:1) showed the starting material and the product was the same spot. The reaction mixture was poured into H2O, extracted with EA. The organic phase was dried over anhydrous Na2SO4, concentrated in vacuum to give a residue, which was purified by column chromatography (silica gel, eluting with PE:EA=1:1) to afford the pure methyl 4-allyl-3-(4-benzyloxyazepan-1-yl)sulfonyl-benzoate (630.00 mg, 1.42 mmol, 52.80% yield) as light yellow solid.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[N:17]1([S:21]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[C:30]([Cl:32])[C:29](F)=[CH:28][C:27]=2[F:34])(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18]1.C12(CO)CC3CC(CC(C3)C1)C2.[CH2:48]1[C:50]2([CH2:55][CH2:54][CH:53]([CH2:56][OH:57])[CH2:52][CH2:51]2)[CH2:49]1>>[N:17]1([S:21]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:57][CH2:56][CH:53]3[CH2:54][CH2:55][C:50]4([CH2:48][CH2:49]4)[CH2:51][CH2:52]3)=[CH:28][C:27]=2[F:34])(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18]1
Reactant: OCC1CCC2(CC1)CC2
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with N-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide and to replace adamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, the title compound was obtained as a colorless solid (0.61 g, 53%): 1H NMR (300 MHz, CDCl3) δ 8.70-8.57 (m, 1H), 8.17-8.09 (m, 1H), 6.76-6.66 (m, 1H), 4.32-4.19 (m, 4H), 3.96-3.87 (m, 2H), 2.35-2.20 (m, 2H), 2.03-1.70 (m, 5H), 1.39-1.20 (m, 2H), 1.02-0.86 (m, 2H), 0.38-0.16 (m, 4H); MS (ES+) m/z 431.1 (M+1), 433.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:17])=[CH:4][CH:3]=1.Cl[C:19](OC(Cl)(Cl)Cl)=[O:20]>C1(C)C=CC=CC=1>[Br:17][C:5]1[C:6]2[CH2:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:11])[O:9][C:10]=2[C:2]([N:1]=[C:19]=[O:20])=[CH:3][CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)C1(C)Cc2c(Br)ccc(N)c2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C)Cc2c(Br)ccc(N=C=O)c2O1
Yield: 104.2 %

Procedure:
By the method of Example 1, Step F, 1.6 grams (0.005 mole) of 7-amino-4-bromo-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran and 1.0 gram (0.005 mole) of trichloromethyl chloroformate were reacted in 60 mL of toluene, yielding about 1.7 grams of 4-bromo-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran-7-yl isocyanate. The product was taken to the next step without further characterization.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:15]([F:38])=[C:16]([CH:35]=[CH:36][CH:37]=1)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C@H:20]([CH3:34])[CH2:19]1.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=1>C1COCC1.CCOC(C)=O>[F:38][C:15]1[C:14]([NH:13][C:5]([NH:48][C:49]2[CH:54]=[CH:53][N:52]=[C:51]([CH3:55])[CH:50]=2)=[O:11])=[CH:37][CH:36]=[CH:35][C:16]=1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C@H:20]([CH3:34])[CH2:19]1
Reactant: C[C@@H]1CN(Cc2cccc(N)c2F)CCN1C(=O)OCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)ccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)Nc2cccc(CN3CCN(C(=O)OCc4ccccc4)[C@H](C)C3)c2F)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
To a 0° C. solution of triphosgene (150 mg, 0.50 mmol, 0.35 equiv) in THF (15 mL) was slowly added via cannula a solution of (R)-benzyl 4-(3-amino-2-fluorobenzyl)-2-methylpiperazine-1-carboxylate (500 mg, 1.4 mmol, 1.0 equiv) and DIPEA (485 μL, 18.5 mmol, 2.0 equiv) in THF (15 mL) over approximately 15 minutes. The solution was stirred for an additional 20 min at 0° C., and 4-amino-2-methylpyridine was then added. After stirring at room temperature overnight, the reaction was diluted with EtOAc, washed with aq. satd. NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase preparative HPLC provided (R)-benzyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate (180 mg, 27%). LCMS m/z (APCI)=492.3 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:14]>CO>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(CO)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)Cc1ccc(CO)cc1
Reaction time: 3 h

Procedure:
To 2-(4-(hydroxymethyl)phenyl)acetic acid in MeOH at 0° C. was added TMS-CHN2. The solution was stirred for 3 h then quenched with a few drops of AcOH. The solvents were evaporated. Column chromatography (SiO2, 3-15% EtOAc/Hex) gave pure methyl 2-(4-(hydroxymethyl)phenyl)acetate (E132).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:10]2[C:11]([NH:13][C:14](=[O:15])[C:9]=12)=[O:12].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(OCC)C>[N:19]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][CH:16]=[C:10]3[C:11]([NH:13][C:14](=[O:15])[C:9]=23)=[O:12])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C1COCCN1
Reactant: O=C1NC(=O)c2c(CCCCCCBr)cccc21
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCCCCN3CCOCC3)cccc21

Procedure:
6-Bromohexylphthalimide (633 mg; 2.0 mmoles) and morpholine (0.35 mg; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.[CH:41]1([O:46][CH2:47][CH2:48]O)[CH2:45][CH2:44][CH2:43][CH2:42]1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[ClH:19].[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:48][CH2:47][O:46][CH:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: OCCOC1CCCC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOC1CCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 118.1 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (355 mg, 1.4 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (150 mg, 0.47 mmol), (prepared as described for the starting material in Example 2), 2-(cyclopentyloxy)ethanol (91 mg, 0.7 mmol), (U.S. Pat. No. 4,515,814), and tributylphosphine (284 mg, 1.4 mmol) in methylene chloride (6 ml) at 0° C. The mixture was then allowed to warm to ambient temperature and stirred for 3.5 hours. Ether (3 ml) was added and the insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was dissolved in acetone and 1M ethereal hydrogen chloride (0.6 ml) was added. The mixture was left to stand for 60 hours and the precipitate was collected by filtration, washed with acetone and dried to give 4-(4-chloro-2-fluoroanilino)-7-(2-cyclopentyloxyethoxy)-6-methoxyquinazoline hydrochloride (130 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2(O)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=3)(O)[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>CC(C)=O.O.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[C:23]3[C:18]([C:17]([C:25]#[C:26][C:27]4[CH:28]=[CH:29][C:30]([Br:33])=[CH:31][CH:32]=4)=[C:16]4[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]4)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=1
Reactant: OC1(C#Cc2ccc(Br)cc2)c2ccccc2C(O)(C#Cc2ccc(Br)cc2)c2ccccc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: Brc1ccc(C#Cc2c3ccccc3c(C#Cc3ccc(Br)cc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 9,10-bis-(4-bromo-phenylethynyl)-9,10-dihydro-anthracene-9,10-diol (2.0 g, 3.5 mmol) in aceton (25 ml), a solution of tin(II)chloride dihydrate (1.82 g, 8.05 mmol) in a mixture of water (15 ml) and acetic acid (15 ml) is added within 15 minutes. The obtained suspension is stirred for another 2.5 hours at ambient temperature, and then the solid is filtered off to give a first crop the title compound. Over night another crop of product crystallizes from the mother liquors, and the combined crops are recrystallized from anisol (30 ml) to give the title compound as orange needles. DSC: mp=305° C. MS: 534 (correct isotope pattern). Elementary analysis: C, 67.45; (calcd. 67.19); H, 3.23; (calcd. 3.01).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH3:22])[CH:16]=[CH:15]2.[I:23]I>ClC1C=CC=CC=1>[I-:23].[F:11][C:12]1[CH:21]=[CH:20][C:19]2[N:18]3[C:2]4[CH:3]=[CH:4][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=5[N+:1]=4[CH:22]=[C:17]3[CH:16]=[CH:15][C:14]=2[CH:13]=1
Reactant: c1ccc2ncccc2c1
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: II
Solvent: Clc1ccccc1
Product: Fc1ccc2c(ccc3c[n+]4c5ccccc5ccc4n32)c1
Product: [I-]

Procedure:
A mixture of 614 g. of quinoline, 192 g. of 6-fluoroquinaldine [J. Org. Chem. 42, 911 (1977)], 2.0 l. of chlorobenzene and 602 g. of iodine is stirred at 25°-30° C. for 2 hours, then heated at 95°-100° C. for 90 hours. The mixture is cooled and the precipitate is collected, washed with cold chlorobenzene and suspended in 1.5 l. of methanol. The methanol suspension is stirred with 150 ml. of hydrazine hydrate and the resulting solid 10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration; m.p. 330°-334° C., after crystallization from methanol.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].C(=O)(O)O.[NH2:12][C:13]([NH2:15])=[NH:14].C(=O)=O>O>[C:1]([O-:7])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[NH2:14][C:13]([NH2:15])=[NH2+:12].[NH2:14][C:13]([NH2:15])=[NH2+:12]
Reactant: N=C(N)N
Reactant: O=C(O)CC(=O)O
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NC(N)=[NH2+]
Product: O=C([O-])CC(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Malonic acid (1.00 g, 9.61 mmol) was dissolved in 30 ml of distilled water. Guanidine carbonate (1.73 g, 9.61 mmol) was added via syringe at room temperature (carbon dioxide gas was evolved) and the reaction was stirred at room temperature for 24 hours. The water was removed in vacuo with heating to approximately 90° C. for 4 hours. The product was isolated as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[C:4]([F:21])[C:3]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[C:29]1([C:35]2[CH:39]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][C:48]=3[O:55][CH:56]([CH3:58])[CH3:57])[N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:29]1([C:35]2[CH:39]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([CH2:53][N:8]([S:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]4[CH:5]=[C:4]([F:21])[C:3]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:2]([F:1])[CH:7]=4)=[CH:49][C:48]=3[O:55][CH:56]([CH3:58])[CH3:57])[N:36]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)Oc1cc(CO)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Reactant: CCOC(=O)CCc1c(F)cc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(F)cc(N(Cc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC(C)C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reaction time: 16 h

Procedure:
A solution of ethyl 3-(2,6-difluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (0.425 g, 1.03 mmol), {4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxyphenyl}methanol (0.315 g, 0.790 mmol) and triphenylphosphine (0.312 g, 1.19 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature, diethyl azodicarboxylate (40% toluene solution, 0.540 mL, 1.19 mmol) was added and the mixture was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give ethyl 3-(4-{{4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxybenzyl}[(2-nitrophenyl)sulfonyl]amino}-2,6-difluorophenyl)propanoate as a yellow oil. To a solution of the obtained oil and mercaptoacetic acid (0.169 g, 1.84 mmol) in N,N-dimethylformamide (15 mL) was added lithium hydroxide monohydrate (0.154 g, 3.68 mmol), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (0.431 g, yield 90%, 2 steps) as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].CN(C=O)C.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[O:30][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To (E)-2-(2-bromomethylphenyl)-2-methoxyimino-N-methylacetamide (0.72 g, 2.5 mmol), added were dry DMF (5.0 ml), 2,5-dimethylphenol (0.46 g, 3.75 mmol) and potassium carbonate (0.69 g, 5.0 mmol), and the reaction mixture was stirred at room temperature for 4 hours. Then, water (100 ml) was added to the reaction mixture which was then extracted with ethyl acetate (100 ml). The extract was washed with water (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.57 g) as colorless crystals (yield, 69.8%).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]([C:17]1[NH:21][CH:20]=[C:19]([NH:22][C:23]2[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[N:26]=[C:25]([N:33]3[CH2:37][CH2:36][CH2:35][CH:34]3[C:38](OC)=[O:39])[N:24]=2)[CH:18]=1)([CH3:16])[CH3:15]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:38]([CH:34]2[CH2:35][CH2:36][CH2:37][N:33]2[C:25]2[N:24]=[C:23]([NH:22][C:19]3[CH:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[NH:21][CH:20]=3)[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[N:26]=2)=[O:39])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCCN1c1nc2c(c(Nc3c[nH]c(C(C)C)c3)n1)CCCC2
Reactant: Nc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)Nc3ccc(F)nc3)nc3c2CCCC3)c[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (1.41 g, 12.5 mmol) in THF (30 mL) was added 2M solution of isopropylmagnesium chloride in THF (6.2 mL, 12.4 mmol) dropwise at 0° C. The resultant mixture was stirred at the same temperature for 20 min followed by the dropwise addition of a solution of methyl 1-(4-(5-isopropyl-1H-pyrrol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxylate (1.2 g, 3.12 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with saturated aqueous NH4Cl (40 mL) and was extracted with EtOAc (3×50 mL). The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product which was purified by column chromatography on silica (100-200 mesh using 1% MeOH-DCM system as eluent to afford N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrrol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide (750 mg) as racemate. The enantiomers were separated by chiral HPLC to afford (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8 tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide (200 mg), and its (S) enantiomer. 1H NMR (400 MHz, CDCl3, freebase) δ (ppm): 1.10-1.30 (m, 6H), 1.80-2.20 (m, 7H), 2.35-2.46 (m, 2H), 2.58-2.80 (m, 3H), 2.81-2.99 (m, 1H), 3.58-3.77 (m, 2H), 4.75 (brs, 1H), 6.20 (s, 1H), 6.83 (dd, 1H), 6.95 (s, 1H), 7.91 (s, 1H), 8.18 (s, 1H), 10.80 (brs, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH:12](O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:36]#[N:37])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:20])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:36]#[N:37])[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C(=O)OCC[Si](C)(C)C)C(O)c1ccncc1
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccnc(C#N)c1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-hydroxy-3-(4-pyridyl)propionate (0.60 g, 2.0 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.50 g, 2.2 mmol) was added thereto. The reaction mixture was stirred at room temperature for 16 hrs and subjected to a silica gel (35 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (4:1, v/v) were collected and concentrated. The residue was dissolved in acetonitrile (4 ml), and trimethylsilyl cyanide (0.39 g, 3.9 mmol) and N,N-dimethylcarbamoyl chloride (0.38 g, 3.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 50 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution, 1 N hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (20 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (0.54 g, 85%).