Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.C(C1C=CC=CC=1[N:16](C(=O)N)[C@H:17]([C:25]([NH2:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OC)=O.[C:31]([O:34][CH2:35]C)(=[O:33])[CH3:32]>>[N:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:32]=2[C:31](=[O:33])[O:34][C:35]=1[NH:27][C:25](=[O:26])[C@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:16]
Reactant: COC(=O)c1ccccc1N(C(N)=O)[C@@H](Cc1ccccc1)C(N)=O
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1nc2ccccc2c(=O)o1
Reaction time: 3 h

Procedure:
5 ml of concentrated sulfuric acid was added to 400 mg of 1-N-(2-carbomethoxyphenyl)-carbamoylphenylalanine amide (Preparation IX). The mixture was stirred for 3 hours and poured onto a mixture of ethyl acetate and ice-cold sodium bicarbonate solution. The mixture was extracted with ethyl acetate after neutralization. The organic extract, dried over magnesium sulfate, was evaporated to a solid. Recrystallization from ethyl acetate-hexane yielded 250 mg of N-(4H-3,1-benzoxazin-4-on-2-yl)-phenylalaninamide; m.p. 215°-216° C. 'H NMR 3.0 (m, 2H, PhCH2), 4.5 (m, 1H, NCH), 7.8-8.2 (overlapping peaks, 9H, ArH). IR: 3380, 3180, 1750, 1730, 1660, 1640 cm-1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:39](=[CH:43]\[CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)/[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31](/[C:39](=[CH:43]\[CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)/[C:40]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Yield: 51.1 %

Procedure:
A solution of triphenylphosphine (120 mg, 0.46 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (92 mg, 0.52 mmol). The reaction mixture was stirred at 0° C. until the reaction mixture became homogeneous. The resulting light purple reaction mixture was then treated with (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid (100 mg, 0.30 mmol), and the reaction mixture was stirred at 0° C. for 20 min. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-aminothiazole (46 mg, 0.46 mmol) and pyridine (0.044 mL, 0.55 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded the (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-acrylamide (63 mg, 50%) as a yellow oil: EI-HRMS m/e calcd for C18H19ClN2O3S2 (M+) 410.0526, found 410.0529.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.O1CCCC1.[Pd]>[C:1]([NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nccc(C=Cc2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1nccc(CCc2ccc(N)cc2)n1
Yield: 91.1 %

Procedure:
A mixture of 2-acetamido-4-[2-(4-nitrophenyl)vinyl]pyrimidine (8.52 g) in ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium on carbon (2 g) under atmospheric pressure of hydrogen gas for 6 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 2-acetamido-4-[2-(4-aminophenyl)ethyl]pyrimidine (7.0 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:20])[CH:9]([OH:19])[CH2:10][C:11]#[C:12][C:13]#[C:14][CH:15]([OH:18])[CH:16]=[CH2:17].CO[C:23](OC)([CH3:25])[CH3:24].[CH3:28][C:29]1C=CC(S(O)(=O)=O)=[CH:33][CH:34]=1.O>C1COCC1>[CH2:7]([C@H:8]1[O:20][C:23]([CH3:25])([CH3:24])[O:19][C@@H:9]1[CH2:10][C:11]#[C:12][C:13]#[C:14][C@@H:15]([C:16]1[CH:33]=[CH:34][CH:29]=[CH:28][CH:17]=1)[OH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: COC(C)(C)OC
Reactant: C=CC(O)C#CC#CCC(O)C(O)CCCCCCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1CC#CC#C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 722.7 %

Procedure:
To a stirred mixture of Panaxytriol derivative (1R,7R,8R)-1-phenyl-2,4-pentadecadiyne-1,7,8-triol (12.8 mg, 39.0 μmol, 1.0 equiv) and 2,2-dimethoxypropane (40.6 mg, 390 μmol, 10 equiv) in dry THF (1.0 mL) was added p-TsOH.H2O (about 1 mg) at 0° C. The cooling bath was removed immediately and the mixture was stirred at room temperature. After 40 min, the reaction was quenched with a saturated solution of NaHCO3 (1 mL). The mixture was extracted with dichloromethane (4 times). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude mixture was purified by gradient flash column chromatography (hexanes/EtOAc=9:18:17:1) to afford the title compound (14.0 mg, 97%) as a pale yellow oil: 1H-NMR (CDCl3, 400 MHz) δ 7.52-7.50 (m, 2H), 7.40-7.32 (m, 3H), 5.50 (s, 1H), 3.83-3.78 (m, 1H), 3.75-3.71 (m, 1H), 2.67-2.56 (m, 2H), 2.30 (br s, 1H), 1.68 (br s, 1H), 1.62-1.26 (m, 12H), 1.40 (s, 6H), 0.88 (t, J=7.0 Hz, 3H); 13C-NMR (CDCl3, 100 MHz) δ 139.75, 128.70, 128.62, 126.62, 108.72, 80.46, 78.11, 77.57, 75.53, 71.35, 66.51, 64.97, 32.90, 31.77, 29.62, 29.13, 27.40, 27.03, 25.94, 23.60, 22.62, 14.07.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([OH:18])=O)[CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C[N:21](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.N>C(Cl)Cl.C1COCC1>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:21])=[O:18])[CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(-c2ccccc2)cc2cc[nH]c12
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccccc2)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-phenyl-1H-indole-7-carboxylic acid (10.0 g, 42.0 mmol) in a mixture of CH2Cl2 (100 mL) and THF (100 mL) at room temperature, N-(3-Dimethylaminopropy)-N′-ethylcarbodiimide hydrochloride (9.66 g, 50.4 mmol), 1-Hydroxybenzotriazole hydrate (6.81 g, 50.4 mmol) and ammonia (2 M in methanol, 168 mmol, 84 mL) were added. The reaction mixture was stirred at room temperature for 24 hours. All solvent were evaporated and the reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organic phase washed with brine, dried over Mg2SO4 and concentration to give the product which is pure enough for next reaction (10 g, 100%).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]1=[O:20])#[N:2].Cl.N[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>O>[S:29]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:2]=[C:1]1[CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]1=[O:20]
Reactant: CCOC(=O)CC1Sc2ccccc2N(CC#N)C1=O
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: O
Product: CCOC(=O)CC1Sc2ccccc2N(Cc2nc3ccccc3s2)C1=O
Temperature: 180 °C
Yield: 68.7 %

Procedure:
A mixture of 208 mg of ethyl 2-(4-cyanomethyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)acetate and 116 mg of 2-aminothiophenol hydrochloride was heated at 180° C. for 15 minutes to fuse them. After the mixture had been cooled, water was added, and then extracted with ethyl acetate. After the drying of the organic layer over anhydrous magnesium sulfate, the solvent was distilled off. The resulting oily matter was purified by silica gel chromatography to give 196 mg of the title compound. The structural formula and physical data of this compound are shown in Table 15.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].F[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.O>C1COCC1>[N+:22]([C:21]1[C:16]([O:14][CH:12]2[CH2:13][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11]2)=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=[N+]([O-])c1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ncccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.30 g, 57.64 mmol) was added portionwise into a solution of 1-Boc-3-(hydroxy)azetidine (9.94 g, 57.64 mmol) in anhydrous THF (110 mL) at 0° C. and stirred for 0.5 hour. A solution of 2-fluoro-3-nitro-pyridine (7.80 g, 54.9 mmol) in anhydrous THF (15 mL) was added drop wise and the mixture allowed to warm to ambient temperature overnight. The mixture was cooled in an ice-bath and water (50 mL) added. The product was extracted with EtOAc, washed with water, brine and dried (Na2SO4). The product was purified by flash-column chromatography (petroleum ether (40-60° C.)/DCM) to yield the title compound as a yellow solid (4.37 g, 27%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([OH:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:18][C@H:19]1[CH2:23][NH:22][C@H:21]([C:24](O)=[O:25])[CH2:20]1>>[ClH:3].[CH2:5]([O:17][C:24](=[O:25])[C@@H:21]1[CH2:20][C@@H:19]([OH:18])[CH2:23][NH:22]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Product: CCCCCCCCCCCCOC(=O)[C@@H]1C[C@@H](O)CN1
Product: Cl
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Thionyl chloride (15.5 g, 130 mmol) at 25 to 30° C. was added with stirring to 1-dodecanol (190 g, 1.02 mol). After adding trans-4-hydroxy-L-proline (15 g, 114.4 mol), the suspension was stirred for 5 hours at 100° C. The 1-dodecanol was distilled off under reduced pressure from the now clear reaction solution, and the cooled crystalline residue was dissolved in methanol and filtered. The solvent was distilled off under reduced pressure and distillation was interrupted when crystallization started. The residue was precipitated from diethyl ether, then the precipitate was filtered off and washed with diethyl ether. Yield: 35.3 g (105.1 mmol, 92% of theory) of a white crystalline powder. 1H-NMR (CD3SOCD3)δ=0.86 (3H, t), 1.25 (18H, m), 1.61 (2H, m), 2.08 (1H, m), 2.18 (1H, m), 3.06 to 3.3 (partly under H2O signal, m), 4.16 (2H, m) 4.45 (2H, m), 5.53 (1H, m), 9.5 to 10 ppm (2H, broad); 13C-NMR (CD3SOCD3)δ=168.8 (s), 68.4 (d), 65.8 (t), 57.4 (d), 53.2 (d), 37.0(t), 31.2 (t), 28.94 (t), 28.90 (t), 28.86 (t), 28.81 (t), 28.60 (t), 28.51 (t), 27.8 (t), 25.08(t) 22.0 (t), 13.9 ppm (q). MS (ESI) m/e=300.1 (M+of the cation).
Reaction SMILES: NC1C=C([Cl:8])C(OC)=CC=1C(=O)C.C(C1N=C(C(Cl)=O)SC=1)(C)C.[C:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[NH:36][C:37]([C:39]1[S:40][CH:41]=[C:42]([CH:44]([CH3:46])[CH3:45])[N:43]=1)=[O:38])(=[O:27])[CH3:26]>>[C:25]([C:28]1[C:29]([NH:36][C:37]([C:39]2[S:40][CH:41]=[C:42]([CH:44]([CH3:46])[CH3:45])[N:43]=2)=[O:38])=[C:30]([Cl:8])[C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)(=[O:27])[CH3:26]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Reactant: COc1cc(C(C)=O)c(N)cc1Cl
Agent: CC(C)c1csc(C(=O)Cl)n1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl
Yield: 69 %

Procedure:
Compound 217d was synthesized from compounds 201g and 214 as a beige solid in 69% yield, according to the procedure as described for compound 217a. MS (ESI, EI+): m/z=354 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:23][C:22]4[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:21]=4[F:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Cc1ccc(F)c(N)c1
Product: Cc1ccc(F)c(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-fluoro-5-methylaniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-fluoro-5-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.11 (dd, 1H, J=1.8 and 8.1 Hz), 7.94 (d, 1H, J=2.7 Hz), 7.08-6.84 (m, 4H), 6.74-6.67 (m, 1H), 6.64-6.59 (m, 1H), 4.27 (s, 4H), 2.28 (s, 3H); 19F NMR (282 MHz, CDCl3): −38659, −47267; LCMS: purity: 100%; MS (m/e): 371 (MH+).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>O>[CH2:1]([OH:23])[C@H:2]1[O:7][CH:6]([OH:8])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[OH2:7]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
For this purpose, a composition was prepared by mixing 18.5 parts of liquid saccharose and 68 parts of water at 60° C. 0.2 parts of stabiliser formed by carrageenans and xanthan gum and 3.5 parts of glucose syrup were then added. 10 parts of apple puree and colouring agent were added and the mixture was pasteurised at 86° C. for 23 seconds, the composition was cooled to 4° C. and left to rest for 4 hours at this temperature. It was brought to 100 parts by the addition of lemon aroma.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][CH2:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[C:11](=[O:31])[C@:10]([CH2:33]C3COC(C)(C)O3)([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[C:42](C)=[O:43].[OH:45]S(O)(=O)=O.O=[Cr](=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][CH2:23][S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])[C:11](=[O:31])[C@:10]([CH2:33][C:42]([OH:43])=[O:45])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CC[C@@H](CCS(=O)(=O)CC)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Solvent: C1CCOC1
Product: CC[C@@H](CCS(=O)(=O)CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S)-1-(ethylsulfonyl)pentan-3-yl)-3-methylpiperidin-2-one (70.0 mg, 0.115 mmol; Example 202, Step C) in THF (1.15 mL) at 25° C. was added a solution of Jones' Reagent (chromium (VI) oxide) (138 μL, 0.172 mmol) and the reaction mixture was stirred for 1 hour. The reaction mixture was partitioned between water and EtOAc (2×), and then the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by reverse phase high-pressure liquid chromatography (Eclipse column (Agilient Technologies, Santa Clara, Calif.), eluent: 30-75% acetonitrile/water) provided the title compound as an off-white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:21][CH2:22][Cl:23].Cl>O.O1CCCC1>[Cl:23][CH2:22][CH2:21][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH3:19])=[O:17]
Reactant: ClCCBr
Reactant: COC(=O)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CCCl
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 75.8 %

Procedure:
The reaction vessel was dried and, under an argon atmosphere, 75.9 grams (0.75 mole) of diisopropylamine and 450 ml of tetrahydrofuran was added. The stirred solution was cooled to -70° C. and 48.0 grams (0.75 mole-484 ml of 1.5 molar in hexane) of n-butyl lithium was added. Upon completion of addition the reaction mixture stirred for 20 minutes and, at -70° C., 68.9 grams (0.675 mole) of methyl isobutyrate was added dropwise. Upon completion of addition the reaction mixture stirred for an additional 20 minutes and, at -70° C., 108.0 grams (0.75 mole) of 1-bromo-2-chloroethane was added dropwise. The reaction mixture was allowed to warm to ambient temperature where it stirred for 16 hours. After this time 500 ml of water, then 85 ml of concentrated hydrochloric acid, were added dropwise to the reaction mixture. Upon completion of addition the reaction mixture stirred for an additional five minutes. The organic layer was separated and washed with 150 ml of aqueous 10% hydrochloric acid. The combined aqueous layers were washed with 150 ml of methylene chloride. The combined organic layers were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to give 84.2 grams of methyl 4-chloro-2,2-dimethylbutanoate; b.p. 80°-84° C./15 mm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13](I)[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.[CH3:29][S:30]SC>CN(C)C=O.[Zn].[Ni](Br)Br>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([S:30][CH3:29])[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(I)c(O)c(C(C)(C)C)c1
Reactant: CSSC
Agent: Br[Ni]Br
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(SC)c(O)c(C(C)(C)C)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Methyl 3-t-butyl-4-hydroxy-5-iodobenzoate (1.00 g) was dissolved in N,N-dimethylformamide (10 mL), and 2,2′-bipyridine (47 mg), zinc powder (391 mg), nickel bromide (66 mg) and dimethyl disulfide (142 mg) were added to the solution, and then the mixture was stirred at 130° C. for 1 hour. After the reaction solution was filtered, 1N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=12:1) to obtain the title compound (382 mg) as a pale yellow oily substance.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.N1C=CC=CC=1>C(OCC)C>[CH3:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cc2ccccc2[nH]1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1c(C)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of ethyl chlorooxoacetate (22.53 g, 0.165 mol) in diethyl ether (100 mL) was added over a period of 15 minutes to a cooled (0° C.) solution of 2-methylindole (19.7 g, 0.15 mol) and pyridine (14.2 g, 0.18 mol) in diethyl ether (200 mL). The reaction was stirred for two hours at 0° C. under a nitrogen atmosphere. Most of the diethyl ether had evaporated by the end of the two-hour reaction time, and a solid was present. Water (100 mL) was added, and the solid was isolated by filtration and washed with 1:1 diethyl ether/hexane. The solid (27.9 g) was then dissolved in boiling toluene (250 mL) and recrystallized upon cooling to 6° C. The crystals were isolated by filtration, washed with toluene, dried for two hours on the vacuum filter funnel, triturated with water at 75° C. for five minutes, isolated by filtration, and dried for three hours on the filter funnel to provide 17.8 g of ethyl (2-methyl-1H-indol-3-yl)(oxo)acetate as a rust-colored powder.
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[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](O)=[O:27])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1[C:36]2[CH:37]=C[CH:39]=[CH:40][C:35]=2[N:34]=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-:61])=N1)C.C(N(C(C)C)C(C)C)C.NC1CCN(C)CC1>CN(C)C=O>[CH:1]1([N:6]2[CH2:14][C:11]3([CH2:12][CH2:13]3)[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:34][CH:35]5[CH2:40][CH2:39][O:61][CH2:37][CH2:36]5)=[O:27])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: On1nnc2ccccc21
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Agent: CN1CCC(N)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3)ncc21
Reaction time: 0.33 h
Yield: 83.9 %

Procedure:
To a suspension of 0.0189 g (0.0000464 mole) of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-benzoic acid (I-62a) in 3 mL of dimethylformamide was added 0.011 g (0.000082 mole) of 1-hydroxybenzotriazole, 0.0275 g (0.000073 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.07 mL (0.000402 mole) of ethyldiisopropylamine. The mixture was stirred for 20 minutes and then 0.0125 g (0.00011 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-80:20) to give 0.0191 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-N-(tetrahydropyran-4-yl)benzamide (I-63)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C.[CH3:24][O:25][CH2:26]Cl>O1CCCC1>[CH3:24][O:25][CH2:26][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CCc1cc(C=O)ccc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(C=O)cc1CC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Then, 7.0 g of the so-obtained 4-hydroxy-3-(3-methyl-2-butenyl)benzaldehyde was dissolved in 70 ml of tetrahydrofuran, and 19.25 g of N,N-diisopropylethylamine was added to the solution and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction liquid was cooled to 0° C. and 7.0 ml of chloromethyl methyl ether was dropped into the reaction liquid, and the mixture was stirred at room temperature overnight. Then, the reaction liquid was poured into ice water, and the organic layer was extracted with ether, washed with water, dried with anhydrous sodium sulfate, and filtered. The obtained residue was subjected to the column chromatography (260 g of 200-400 mesh Kieselgel 60, hexane/ethyl acetate=6/1, 0.4 kg/cm2), fractions of 50 ml were recovered in sequence, and the 14th to 24th fractions were combined to obtain 7.85 g (yield=91.1%) of 4-methoxymethoxy-3-(3-methyl-2-butenyl)benzaldehyde in the form of a colorless liquid.