Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.C(N)(C)(C)C.[Br:13]Br.[CH3:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([OH:26])[CH:20]=[CH:21][CH:22]=2)[N:17]=1>C(Cl)Cl>[Br:13][C:20]1[C:19]([OH:26])=[C:18]2[C:23]([CH:24]=[CH:25][C:16]([CH3:15])=[N:17]2)=[CH:22][CH:21]=1
Reactant: BrBr
Reactant: Cc1ccc2cccc(O)c2n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC(C)(C)N
Product: Cc1ccc2ccc(Br)c(O)c2n1
Temperature: -25 °C
Yield: 60.7 %

Procedure:
To a 250 mL flask was added toluene (150 mL) and t-BuNH2 (7.26 mL, 69.1 mmol). The solution was cooled to −25° C. and bromine (1.95 mL, 38.0 mmol) was added. The solution was cooled to −78° C. and 2-methylquinolin-8-ol (5.5 g, 34.6 mmol) was added as a CH2Cl2 solution (15 mL). The reaction mixture was then gradually warmed to ambient temperature over 6 hours. The mixture was washed with water (50 mL) and then treated with 3.0 M aqueous NaOH (250 mL). This provided copious amounts of precipitate, which went into solution after about 600 mL water was added. The layers were mixed and separated. The alkaline extract was carefully acidified with concentrated HCl (about 50 mL). The solution was extracted with CH2Cl2 (4×200 mL), and the combined extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The original water wash was found to contain a significant amount of product, so 10 mL 1M HCl was added and the acidic solution was extracted with CH2Cl2 (2×75 mL) and these layers were also washed with brine, dried over Na2SO4, filtered and concentrated. The organic phases were combined to provide 5.0 g (60%) of the desired product as a red/brown solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][CH:14]3[N:9]([CH2:10][CH2:11][C:12](=O)[CH2:13]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:19]1([N:18]=[C:12]2[CH2:11][CH2:10][N:9]3[CH:14]([CH2:15][CH2:16][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8]3)[CH2:13]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCN2CC(c3ccccc3)CCC2C1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(N=C2CCN3CC(c4ccccc4)CCC3C2)cc1

Procedure:
The ketone (III) (5.25 g.) was dissolved in 100 ml. toluene and 2.13 g. aniline. A small amount of pTSA was added and the solution was refluxed overnight using a Dean-Starke trap. The solvent was removed in vacuo Yield, 6.9 g. The semi-solid still had some ketone present (IR spectrum) so the residue was recycled using 1 g. aniline. The reaction was worked up as above and the crude anil showed no ketone. Yield, 7.2 g. (6.97 g. theoretical; probably excess aniline present).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[CH:43][C:33]=1[O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>CC#N.CO.CC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:45]5[CH:44]=[CH:43][C:33]([O:34][CH2:35][CH2:36][N:37]6[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]6)=[C:32]([O:31][CH3:30])[CH:46]=5)[CH:3]=4)[NH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCCN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Solvent: CO
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc5[nH]ccc5c4)c3c2)ccc1OCCN1CCNCC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate B) (92 mg, 0.20 mmol) in CH3CN (2 mL) in a Personal Chemistry microwave reaction vial was added 1-(2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine (Intermediate AM) (72 mg, 0.20 mmol), bis(triphenylphosphine)-palladium(II) dichloride (20 mg, 0.028 mmol), and 1 M Na2CO3 (2 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 25 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and concentrated in vacuo to give Intermediate AN. The residue was dissolved in MeOH (3 mL) and acetone (2 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 50° C. for 2 h, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue that was subjected to preparatory HPLC to yield the title compound. HPLC retention time: 1.29 minutes; MS ESI (m/z) 468.6 (M+1)+, calc. 467.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19](#[N:23])[CH:20]([CH3:22])[CH3:21].Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[CH3:26][Si:25]([CH3:28])([CH3:27])[C:20]([CH3:22])([CH3:21])[C:19]#[N:23]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)C#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C#N)[Si](C)(C)C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
2-(Trimethylsilyl)isobutyronitrile was prepared by the following procedure. To a stirred solution of 30.2 g (0.29 mole) of diisopropylamine in 220 ml of THF under argon was added at 0°-5° 184 ml of 1.58 M n-butyl lithium/hexane at a rate such that the temperature did not exceed 6°. After 15 min. 20 g (0.29 mole) of isobutyronitrile was added at 0°-5°. After 20 min., 47.3 g (0.44 mole) of chlorotrimethylsilane was added. After standing 18 h at room temperature, the mixture was filtered under argon and the filtrate was evaporated in vacuo to a solid which was extracted with ether and filtered. The filtrate was evaporated in vacuo to give 30.51 g (74%) of 2-(trimethylsilyl)isobutyronitrile as a pale yellow water-sensitive solid. Anal. Calcd. for C7H15NS: C, 59.50; H, 10.70; N, 9.92. Found: C, 59.60; H, 11.07; N, 9.74. I.R. (CCl 4): 2220 cm-1 (C≡N), 847 cm-1, 1255 cm-1 (SiMe3). NMR (90 MHz): δ0.22 (9H, SiCH3); δ1.35 (6H, CCH3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([C:35]([OH:37])=O)[N:11]([C:16]([C:18]1[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][CH:23]=1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:38][CH2:39][CH2:40][OH:41].C(N(C(C)C)CC)(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(=O)([O-])O.[Na+]>[C:24]([C:21]1[N:20]=[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)[C:18]([C:16]([N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[C@H:10]([C:35]([NH:38][CH2:39][CH2:40][OH:41])=[O:37])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:17])=[CH:23][N:22]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: NCCO
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(=O)NCCO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
3-[(tert-Butoxycarbonyl)amino]-N-({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)-N-(2-methylpropyl)-L-alanine (125 mg), 2-aminoethanol (60 mg) and diisopropylethylamine (250 μl) were dissolved in DMF (10 ml), BOP reagent (500 mg) was added and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:0) was concentrated under reduced pressure to give the object compound (110 mg).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cl-].[NH+]1C=CC=CC=1.C(OCC)(=O)C>O>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(F)ccc3c1C2=O
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(F)ccc21
Temperature: 160 °C
Reaction time: 12 h

Procedure:
Mixture of 3-fluoro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound V3, 56.6 mg, 0.183 mmol) and pyridinium chloride (0.65 g) was stirred at ambient temperature of 160° C. for 12 hr. The reaction mixture was cooled to room temperature, added with ethyl acetate and water, and the resulting mixture was extracted four times with ethyl acetate. The organic layer was washed with water three times, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was used for the next step without further purification (brown solid, 61.6 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:13]1[CH:29]=[C:17]2[N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:30])[N:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][CH2:10][O:11][C:13]1[CH:29]=[C:17]2[NH:18][CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:30])[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(Cl)c(Cl)c1
Product: O=c1nc(OCCc2ccc(Cl)c(Cl)c2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from 2-(3,4-dichlorophenyl)ethanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:9]1[C:10]([C:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]=3[N:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([CH2:42][C:43]([NH2:45])=[O:44])#[N:41].C1(P(C2C=CC=CC=2)C2C=CC=C3C=2OC2C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=2C3(C)C)C=CC=CC=1.C1(C=CC(=O)C=CC2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:9]1[C:10]([C:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]=3[N:17]=2)=[N:11][C:12]([NH:45][C:43](=[O:44])[CH2:42][C:40]#[N:41])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1
Reactant: N#CCC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc2nc(-c3nc(NC(=O)CC#N)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1

Procedure:
tert-Butyl 2-[3-(bis(tert-butoxycarbonyl)amino)-6-bromo-pyrazin-2-yl]-6-methyl-benzimidazole-1-carboxylate (150 mg, 0.2481 mmol), 2-cyanoacetamide (31.28 mg, 0.3722 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (8.616 mg, 0.01489 mmol) and 1,5-diphenylpenta-1,4-dien-3-one; palladium (4.544 mg, 0.004962 mmol) heated with dicesium carbonate (161.7 mg, 0.4962 mmol) in dioxane for 4 hours at 60° C. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography eluting with 20% EtOAc/petroleum ether to give the sub-title product as pale yellow solid which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]3[C:16]=2[CH2:17][N:18]([CH3:28])[C:19]3=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C(O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]3[C:16]=2[CH2:17][N:18]([CH3:28])[C:19]3=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1Cc2c(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN1Cc2c(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc(N)c2C1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 165.2 %

Procedure:
A mixture of 4-(2-methyl-7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (654 mg, 1.0 mmol), iron powder (280 mg, 5.0 mmol), and 1N hydrogen chloride (2 mL, 2.0 mmol) in ethanol (5 mL) is stirred at 80° C. for 1 h under nitrogen atmosphere. After cooling to room temperature, ice and 1N sodium hydroxide are added, the mixture is filtered. The filtrate is extracted with dichloromethane (twice). The combined organic layer is washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 597 mg of 4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester, which is used for the next reaction without purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8](C=O)[CH2:7][CH2:6]1>CO.Cl>[N:5]1([CH2:4][CH2:3][CH2:2][OH:1])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: O=CN1CCN(CCCO)CC1
Agent: Cl
Solvent: CO
Product: OCCCN1CCNCC1
Yield: 63.1 %

Procedure:
A solution of 4-(3-hydroxypropyl)-1-piperazinecarboxaldehyde (4.45 g) in methanol (10 ml) and 4N aqueous hydrogen chloride (15 ml) was stirred at ambient temperature for 3 hours. The volatiles were removed under vacuum and the residue was partitioned between trichloromethane and aqueous sodium hydroxide (40%). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give 3-(piperazin-1-yl)propan-1-ol (2.35 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH:44]1([S:47]([NH2:50])(=[O:49])=[O:48])[CH2:46][CH2:45]1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:50][S:47]([CH:44]5[CH2:46][CH2:45]5)(=[O:49])=[O:48])=[O:30])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)c1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)NS(=O)(=O)C5CC5)ccc4N3)c2)cc1
Yield: 9.7 %

Procedure:
A mixture of 2-(4′-tert-butyl-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70 mg, 0.36 mmol), 4-dimethylaminopyridine (44 mg, 0.36 mmol), cyclopropane sulfonic acid amide (85 mg, 0.72 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(4′-tert-butyl-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (12 mg, 10%) as a light yellow solid: MS (ESI) M+1=517.2.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[N+:14]([C:17]1[CH:18]=[C:19]2[C:24](=O)[O:23][C:21](=[O:22])[C:20]2=[CH:26][CH:27]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[C:19]2[C:20](=[CH:26][CH:27]=1)[C:21](=[O:22])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:24]2=[O:23])([O-:16])=[O:15]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (1.60 g, 42%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (2.00 g, 10.57 mmol) and 4-nitrophthalic anhydride (0.57 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [OH-].[K+:2].[C:3]([NH:13][NH2:14])(=[O:12])[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[C:15](=[S:17])=[S:16]>C(O)C>[C:3]([NH:13][NH:14][C:15]([S-:17])=[S:16])(=[O:12])[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[K+:2]
Reactant: S=C=S
Reactant: NNC(=O)c1ccc(O)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NNC(=S)[S-])c1ccc(O)c(O)c1
Yield: 75.3 %

Procedure:
10 g (178 mmol) of potassium hydroxide was dissolved in 400 ml of ethanol, and 20 g (119 mmol) of protocatechuhydrazide was added thereto under stirring at a temperature of at most 5° C. To this solution, 28.0 ml of carbon disulfide was dropwise added over a period of 10 minutes at a temperature of at most 10° C., and the mixture was stirred at a temperature of from 0 to 10° C. for 30 minutes. Then, the precipitates were collected by filtration, washed with ethanol and dried to obtain 25.3 g (yield: 75.3%) of potassium 3-protocatechuoyldithiocarbazate.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:41]=2[CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([I:46])=[CH:42][C:41]=2[CH:47]2[C:10]3([C:11]4[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:26])[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:50][C:49](=[O:51])[NH:48]2)[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(I)ccc1OC1CCN(C(=O)OC(C)(C)C)C1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)C1
Yield: 23.9 %

Procedure:
In a manner similar to the method described in example 1e, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 5b (1.1 g, 2.8 mmol) was reacted with (R/S)-1-[2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-5-iodo-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (5.3 g, 10 mmol) in toluene (30 mL) at 140° C. for 4 h to give racemic(2′R, 3R, 4′S)-2′-[2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.5 g, 48%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C@@H:34]([NH2:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH3:35][C@H:34]([NH:36][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=1)=[O:23])[C:33]([CH3:38])([CH3:37])[CH3:32]
Reactant: C[C@H](N)C(C)(C)C
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
In a round-bottomed flask 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.27 mmol) was dissolved in DMF (1.2 ml). (S)-3,3-Dimethylbutan-2-amine (0.25 ml, 1.84 mmol) was added followed by HATU (114 mg, 0.30 mmol) and the yellow solution was stirred at room temperature overnight. Water was added and the resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 104 mg (73%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide as a light yellow powder.
Reaction SMILES: Cl.[N:2]([C:5]1[C:6]([NH2:12])=[N:7][CH:8]=[C:9]([F:11])[CH:10]=1)=[N+]=[N-].C(=O)([O-])[O-]>O1CCCC1>[F:11][C:9]1[CH:10]=[C:5]([NH2:2])[C:6]([NH2:12])=[N:7][CH:8]=1
Reactant: [N-]=[N+]=Nc1cc(F)cnc1N
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Nc1cc(F)cnc1N
Reaction time: 1 h
Yield: 92.8 %

Procedure:
The HCl salt of 3-azido-5-fluoropyridin-2-amine (1.90 g, 10.0 mmol) was dissolved in tetrahydrofuran (100 mL) and treated with MP-Carbonate (Argonaut, 11.5 g). After 1 h, the mixture was filtered, rinsed with more tetrahydrofuran, and concentrated. This residue was dissolved in ethanol (50 mL), purged with argon, and 10% palladium on carbon was added (0.15 g). Hydrogen was introduced (1 atm) and the reaction stirred until complete. The catalyst was filtered and the solvent evaporated from the filtrate to give the title compound (1.18 g). MS128.0 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:8].[H-].[Na+].Br[CH2:22][C:23]1[O:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]([CH3:15])=[CH:13][N:14]\1[CH2:22][C:23]1[O:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1)=[O:8]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C)cn1Cc1ccc(C(F)(F)F)o1
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a solution of Example 340A (0.1 g, 0.36 mmol) in 5 mL DMF was added sodium hydride (0.01 g, 0.39 mmol, 95%). The solution was allowed to stir at ambient temperature for 30 min when 2-(bromomethyl)-5-(trifluoromethyl)furan (0.09 g, 0.39 mmol) was added. The reaction was held at ambient temperature overnight and then quenched with water. The crude was extracted with ethyl acetate and the organics washed with water, then dried over MgSO4, filtered, and concentrated. Flash chromatography over silica gel (50% ethyl acetate/hexane) gave 0.05 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.28 (d, J=1.36 Hz, 3H) 3.78 (s, 3H) 5.47 (s, 2H) 6.66 (d, J=2.71 Hz, 1H) 7.11 (d, J=8.81 Hz, 1H) 7.22 (dd, J=3.39, 1.36 Hz, 1H) 7.31-7.39 (m, J=1.36 Hz, 1H) 7.41-7.52 (m, 1H) 7.72 (d, J=2.71 Hz, 1H). m/z 431.0 (M+H)+.