Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH:7]([C:18]([O:20][CH3:21])=[O:19])[CH2:6]1.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])C>O.C(Cl)(=O)OCC1C=CC=CC=1>[CH2:27]([O:26][C:23]([N:4]([CH2:3][CH:2]([CH3:22])[CH3:1])[CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:8][CH:7]([C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)=[O:25])[C:28]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:10]=1
Reactant: COC(=O)C1CC(NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(C)=O
Agent: O=C(Cl)OCc1ccccc1
Solvent: O
Product: COC(=O)C1CC(N(CC(C)C)C(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-tert-Butyl 3-methyl 5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (13.7 g) was dissolved in ethyl acetate (250 ml)-1 M aqueous sodium hydroxide solution (55 ml)-water (200 ml), benzyl chlorocarbonate (7.5 ml) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-50:50) was concentrated under reduced pressure to give the object compound (9.87 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][C:67]5[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)Nc2ccccc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.30 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.011 g (0.12 mmole) of aniline was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 100:0-20:80) to give 0.042 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-phenyl-benzamide (I-38) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:35])([F:34])[C:11]1[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[N:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14]>>[Cl:8][C:5]1[N:4]=[N:3][C:2]([NH:1][C:27]([C:24]2[N:25]=[N:26][C:21]([N:18]3[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C:12]4[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=4[C:10]([F:35])([F:34])[F:9])[CH2:20][CH2:19]3)=[CH:22][CH:23]=2)=[O:28])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(Nc1ccc(Cl)nn1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 24, making variations only as required to use 3-amino-6-chloropyridazine in place of 2,2-(dimethylcyclopropyl)methylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (8% yield). 1H NMR (300 MHz, CDCl3) δ 10.75, 8.62, 8.06, 7.75-7.50, 7.36, 7.03, 4.12-3.76, 3.36. 13C NMR (75 MHz, CDCl3) δ 167.7, 162.2, 160.1, 154.0, 152.3 143.8, 134.1, 132.4, 129.7, 129.6, 127.3, 127.2, 126.94, 126.88, 126.7, 120.7, 112.2, 46.3, 44.6, 44.3, 41.3. MS (ES+) m/z 492.1 (M+1).
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:17]([C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([Cl:34])[CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:29]([C:28]3[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:17]4[C:16]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[CH:26][C:27]=3[Cl:34])=[O:30])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Reactant: c1ccc2c(c1)CNc1cccnc1O2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Oc3ncccc32)c(Cl)c1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 66, reaction of 0.198 g of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine with 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride in dichloromethane in the presence of N,N-diisopropylethylamine gives the product as a solid.
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CON(C)[C:24]([C:26]1[CH:34]=[C:33]2[C:29]([C:30]([CH:36]([C:50]3[CH:58]=[CH:57][C:53]4[O:54][CH2:55][O:56][C:52]=4[CH:51]=3)[C:37]([NH:39][S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])=[O:38])=[CH:31][N:32]2[CH3:35])=[CH:28][CH:27]=1)=[O:25]>O1CCCC1>[O:54]1[C:53]2[CH:57]=[CH:58][C:50]([CH:36]([C:30]3[C:29]4[C:33](=[CH:34][C:26]([C:24](=[O:25])[CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)=[CH:27][CH:28]=4)[N:32]([CH3:35])[CH:31]=3)[C:37]([NH:39][S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=3)(=[O:42])=[O:41])=[O:38])=[CH:51][C:52]=2[O:56][CH2:55]1
Reactant: Cc1ccccn1
Reactant: CON(C)C(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(=O)Cc4ccccn4)ccc23)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (0.53 ml of 1.5M solution in cyclohexane) was added to a stirred solution of 2-methylpridine (0.08 ml, 0.8 mmol) in anhydrous tetrahydrofuran (3 ml) at −70° C. under a nitrogen atmosphere. After 20 minutes a solution of N6-methoxy -N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide (the compound of Example 103, 200 mg, 0.36 mmol) in anhydrous tetrahydrofuran (2 ml) was added to the mixture at −70° C. The mixture was stirred at −70° C. for an additional 2 hours before being warmed to 0° C., and then quenched with the addition of water (5 ml). The mixture was acidified with acetic acid, and extracted with ethyl acetate (100 ml). The organic phase was separated and washed with brine, dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was flash chromatographed using a gradient elution or a mixture of 90% hexane and 10% ethyl acetate, through to 100% ethyl acetate, to give the title compound (95 mg).
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.[CH2:26](O)[CH2:27][C:28]#[CH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:29]([N:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=[N:17]1)[CH2:28][C:27]#[CH:26]
Reactant: C#CCCO
Reactant: c1ccc2[nH]nnc2c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#CCCn1nc2ccccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 222 %

Procedure:
A solution of di-tert-butylazodicarboxylate (3.15 g, 13.4 mmol) in DCM (3 mL) was added dropwise over 30 min at 0° C. to a suspension of benzotriazole (2.40 g, 1.50 mmol), but-3-yn-1-ol (940 mg, 13.4 mmol) and polymer bounded triphenylphosphine (4.40 g, 16.8 mmol, 0.3 mmol/g) in DCM (3 mL). The reaction mixture was stirred at room temperature with a polymix agitation for 2 days and filtered through celite. The organic phase was washed with NH4OH, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 571 mg (3.33 mmol, 25%) of 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C@@H:8]1[CH:12]2[C:13](=O)[NH:14][CH2:15][C:16](=O)[N:11]2[CH2:10][CH2:9]1.[OH-].[Na+]>C1COCC1>[CH2:13]1[NH:14][CH2:15][CH2:16][N:11]2[CH2:10][CH2:9][C@H:8]([OH:7])[CH:12]12
Reactant: O=C1NCC(=O)N2CC[C@H](O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@H]1CCN2CCNCC12
Temperature: 0 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
Into a stirred, cooled (0° C.) suspension of LiAlH4 (3.3 g, 88 mmol) in 60 ml of dry THF, was introduced (8S)-8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (D70, 750 mg, 4.4 mmol) in small portions. The mixture was then allowed to reach rt and stirred for 48 h, after which it was cooled to 0° C. THF was introduced (70 ml), then successively a saturated solution of Na-K-tartrate (5 ml) and a 20% aqueous NaOH solution (5 ml) were dropped into the flask, under vigorous stirring. The suspension was stirred for 30 min at rt, and filtered. The pale filter cake was washed with 100 ml of CHCl3 and the combined filtrates and washings were evaporated in vacuo to give 500 mg of the title compound. From GC-MS analysis 2 diastereomeric products were still observed. Yield 80%.
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[S:8][C:9]([CH3:18])=[C:10]([CH3:17])[C:11]=1[C:12]([O:14]CC)=O)=[O:5])C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(O)C.CN(C)C=O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:25]2[C:12](=[O:14])[C:11]3[C:10]([CH3:17])=[C:9]([CH3:18])[S:8][C:7]=3[NH:6][C:4]2=[O:5])=[CH:22][CH:21]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)Nc1sc(C)c(C)c1C(=O)OCC
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1sc2[nH]c(=O)n(Cc3ccc(Cl)cc3)c(=O)c2c1C
Yield: 68 %

Procedure:
A 1 g quantity of ethyl 2-ethoxycarbonylamino-4,5-dimethyl-3-thiophenecarboxylate and 1 g of 4-chlorobenzylamine were dissolved in a mixture of 3 ml of ethanol and 1 ml of N,N-dimethylformamide and the mixture was allowed to react in a sealed tube at 230° C. for 7 hours. The reaction mixture was concentrated and the residue was recrystallized from an acetone-ethanol-dimethylformamide mixture, giving 0.8 g of 3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione having a melting point of 291° to 292° C. in a yield of 68%.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9].I[CH3:21].Cl>C1COCC1.O.CCCCC>[CH3:21][O:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])[CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: CI
Reactant: O=C(O)c1cc(CO)cc(S(F)(F)(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
108 mg (2.70 mmol) of sodium hydride (as a 60% strength suspension in mineral oil) were deoiled with pentane and then suspended in 5 ml of anhydrous THF. At 0° C., a solution of 250 mg (0.899 mmol) of the compound of Example 37A in 2.5 ml of anhydrous THF was slowly added dropwise to this suspension. After 30 min of stirring at 0° C., 170 μl (2.70 mmol) of iodomethane were added and the cooling bath was removed. Since, according to analytical HPLC, conversion was still incomplete after 6 h at RT, the mixture was once more cooled to 0° C., and a further 560 μl (9.0 mmol) of iodomethane and 36 mg (0.897 mmol) of sodium hydride (60% strength suspension in mineral oil) were added in succession. After 2 h of stirring at RT, about 75 ml of water were added carefully and the reaction mixture was acidified by addition of 1 M hydrochloric acid. The mixture was extracted three times with in each case about 25 ml of ethyl acetate. The combined organic extracts were washed successively with in each case about 30 ml of water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, filtration and removal of the solvent on a rotary evaporator, the residue obtained was triturated with pentane. The crude product obtained in this manner was purified by preparative HPLC (Method 32). Pooling of the product fractions, removal of the solvent on a rotary evaporator and drying under high vacuum gave 153 mg (58% of theory) of the title compound.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[CH2:4][CH2:5][C:6](N)=[O:7].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[CH3:29][C:30]1([CH2:35][CH2:36][C:37](O)=[O:38])[O:34][CH2:33][CH2:32][O:31]1>ClCCl>[CH3:29][C:30]1([CH2:35][CH2:36][C:37]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:9])=[O:38])[O:34][CH2:33][CH2:32][O:31]1
Reactant: CC1(CCC(=O)O)OCCO1
Reactant: NC(=O)CCC(=O)NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC1(CCC(=O)ON2C(=O)CCC2=O)OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
N-Hydroxysuccinamide (0.80 g, 6.9 mmol) followed by 4-methylmorpholine (0.70 g, 6.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.32 g, 6.9 mmol) were added to a 0° C. solution of 3-(2-methyl-1,3-dioxolan-2-yl)propanoic acid (1.00 g, 6.24 mmol) in dichloromethane (12 mL). The solution was allowed to warm to room temperature and was stirred overnight. The reaction mixture was diluted with dichloromethane (10 mL), transferred to a separatory funnel, and washed with water (2×10 mL), saturated aqueous sodium bicarbonate (2×10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1.1 g of 1-{[3-(2-methyl-1,3-dioxolan-2-yl)propanoyl]oxy}pyrrolidine-2,5-dione as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[CH:7]2.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>ClC1C=CC=CC=1>[O:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[N:1]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]1=[O:12]
Reactant: Nc1cccc2ccc(=O)oc12
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Clc1ccccc1
Product: O=c1ccc2cccc(N3CCNCC3)c2o1

Procedure:
N-(coumarin-8-yl)-piperazine was prepared by reacting 8-aminocoumarin with an excess of bis(2-chloroethyl)amine hydrochloride in the presence of potassium carbonate and then of potassium iodide, the reaction being carried out under reflux in chlorobenzene.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:33]3[C:34]([C:37]#[N:38])=[CH:35][CH:36]=[C:32]3[C:12]3([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[O:11][C:10]=2[CH:39]=1)(=O)C.[Li+].[OH-].C1COCC1>CO>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:33]3[C:34]([C:37]#[N:38])=[CH:35][CH:36]=[C:32]3[C:12]3([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]4[CH:20]=[CH:21][C:22]([S:25]([CH:28]([CH3:29])[CH3:30])(=[O:27])=[O:26])=[CH:23][CH:24]=4)[CH2:14][CH2:13]3)[O:11][C:10]=2[CH:39]=1
Reactant: CC(=O)OCc1ccc2c(c1)OC1(CCN(C(=O)c3ccc(S(=O)(=O)C(C)C)cc3)CC1)c1ccc(C#N)n1-2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2cc(CO)ccc2-n2c(C#N)ccc23)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
(1-Cyano-1′-(4-(isopropylsulfonyl)benzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-yl)methyl acetate (16.2 mg, 0.0297 mmol) was treated with 1M LiOH (1 mL), THF (5 mL) and MeOH (1 mL). The mixture was stirred at room temperature over night. The volatiles were removed and the residue was neutralized with 1N HCl. The mixture was extracted with CH2Cl2 (2×). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 7′-(hydroxymethyl)-1-(4-isopropylsulfonylbenzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (11.3 mg, 75%). ESI-MS m/z calc. 505.58, found 506.5 (M+1)+; Retention time 1.49 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.93 (dd, J=8.2, 6.5 Hz, 3H), 7.73 (d, J=8.3 Hz, 2H), 7.32 (d, J=4.0 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.45 (d, J=4.1 Hz, 1H), 5.39-5.30 (m, 1H), 4.51 (s, 2H), 3.81-3.64 (m, 1H), 3.54-3.42 (m, 2H), 3.41-3.37 (m, 1H), 2.20-2.12 (m, 1H), 2.13-2.03 (m, 1H), 2.01 (t, J=5.9 Hz, 1H), 1.57 (dd, J=12.5, 6.2 Hz, 1H), 1.17 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (1.0 g) in dry methylene chloride (14 ml) was added 2,6-lutidine (240 μl) and the mixture was stirred at room temperature. After 10 minutes, tert-butyldimethylsilyl trifluoromethanesulfonate (295 μl) was added via syringe. After 15 minutes the reaction mixture was diluted with ethyl acetate, washed with 1N HCl, water, saturated sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate. Removal of the solvent in vacuo and flash chromatography on silica Eel (ethyl acetate: hexane (1:3)+1% methanol) gave the title compound (293 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [Cl:1][C:2]1[C:3](OC)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.[NH2:13][NH2:14].O>CO>[Cl:1][C:2]1[C:3]([NH:13][NH2:14])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c(OC)n1
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ncc(Cl)c(NN)n1
Reaction time: 8 h

Procedure:
A solution containing 0.35 g (2.0 mmol) of 5-chloro-2,4-dimethoxypyrimidine and 0.35 g (7.0 mmol) of hydrazine hydrate in 2.9 g of methanol was heated at reflux with stirring for 8 hours. The mixture was then cooled causing a precipitate to form water was added until the precipitation appeared to be complete and the precipitate was then recovered by vacuum filtration and allowed to air dry overnight to obtain 0.23 g (66 percent of theory) of the title compound as a white solid. The product melted at 172°-173° C. after changing crystalline form from needles to cube-like shapes in a phenomenon that appeared to involve sublimation.
Reaction SMILES: CO.Cl.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:24]=[C:23]2[C:14]([N:15]3[C:20]([CH2:21][O:22]2)=[N:19][NH:18][C:17](=[O:25])[C@H:16]3[CH3:26])=[CH:13][C:12]=1[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C=O.[BH3-][C:36]#N.[Na+]>C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:24]=[C:23]2[C:14]([N:15]3[C:20]([CH2:21][O:22]2)=[N:19][NH:18][C:17](=[O:25])[C@H:16]3[CH3:26])=[CH:13][C:12]=1[CH:27]1[CH2:32][CH2:31][N:30]([CH3:36])[CH2:29][CH2:28]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4CCNCC4)cc3N21
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4CCN(C)CC4)cc3N21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
To a solution of MeOH (10 mL) and acetic acid (1 mL) was added (R)-7-(2-fluoro-phenyl)-4-methyl-6-piperidin-4-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (0.300, 0.761 mmol) and paraformaldehyde (0.228 g, 7.61 mmol) and the reaction mixture was stirred at rt for 4 h. Then NaCNBH3 (0.096 g, 1.52 mmol) was added and the reaction mixture was stirred for 30 min. The solvent was removed in vacuo and the residue was purified by prep-TLC (eluting with 10% MeOH in DCM) to give (R)-7-(2-fluoro-phenyl)-4-methyl-6-(1-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.160 g, 51%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.50-7.41 (m, 1H), 7.32-7.26 (m, 2H), 7.25-7.19 (m, 1H), 7.09 (s, 1H), 6.86 (s, 1H), 5.02-4.93 (m, 1H), 4.70-4.59 (m, 2H), 3.63-3.46 (m, 2H), 3.04-2.89 (m, 2H), 2.84 (s, 3H), 2.76 (m, 1H), 2.28-2.01 (m, 3H), 1.96-1.83 (m, 1H), 1.52 (d, J=6.4 Hz, 3H). LCMS (Table 1, Method 4) Rt=1.617 min; MS m/z: 409 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[CH3:13][O:14][C:15](=[O:18])[CH2:16]Br>>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([C:3]=1[CH2:16][C:15]([O:14][CH3:13])=[O:18])=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2
Reactant: COC(=O)CBr
Reactant: Cc1ccc2c(c1)CC(C)C2=O
Product: COC(=O)CC1=C(C)Cc2cc(C)ccc21

Procedure:
The above reactions of Example 60(C) are repeated except that the starting materials are 2,5-dimethylindanone and methylbromoacetate. Using the same reaction conditions and techniques there is obtained methyl 2,6-dimethyl-3-indenylacetate.