Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4][NH:5][NH:6][C:7]1[C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=[C:9]2[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:8]=12)#[N:2].O>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:21]([N:18]1[C:9]2[N:10]=[CH:11][C:12]3[C:13](=[O:14])[NH:2][C:1]4[N:6]([N:5]=[CH:4][C:3]=4[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]=3[C:8]=2[CH:20]=[N:19]1)[CH3:22]
Reactant: CCOC(=O)C(C#N)=CNNc1c(C(=O)OCC)cnc2c1cnn2CC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c1[nH]c(=O)c1cnc3c(cnn3CC)c12

Procedure:
351 g of 4-[2-(2-cyano-3-ethoxy-3-oxo-1-propenyl)hydrazino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester are heated in 2 liters of acetic acid containing 50 g of zinc chloride for 24 hours. After this time, the solution is cooled and 2 liters of cold water are added. The precipitated 8-ethyl-5,8-dihydro-5-oxo-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester is filtered off and purified by dissolving in the theoretical amount of sodium hydroxide in water and precipitating the compound with acetic acid, yield 256 g (83%); m.p. 263°-265°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.CC#N.C(=O)=O.C([Li])CCC.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][N:21]=1>C1COCC1>[CH3:1][N:2]1[C:6]([CH:24]([C:23]2[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:27][CH:26]=2)[OH:25])=[CH:5][N:4]=[N:3]1
Reactant: Cn1ccnn1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: Cn1nncc1C(O)c1ccc(C(F)(F)F)nc1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
A 50 mL flask containing 1-methyl-1H-1,2,3-triazole (0.47 g, 5.71 mmol) in dry THF (3 mL) was cooled to −43° C. (CH3CN—CO2 bath). n-Butyllithium (2.5 M in THF, 2.43 mL, 6.08 mmol) was then added dropwise resulting in a light blue suspension. The suspension was stirred at −40° C. for 40 minutes, and then a homogeneous solution of 6-(trifluoromethyl)nicotinaldehyde (1 g, 5.71 mmol) in THF (7 mL) was introduced at −40° C. The resulting homogeneous colorless solution was allowed to warm gradually to room temperature, and after 30 minutes, LC/MS showed that the reaction was complete. The mixture was quenched with water and aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to provide the title compound as a semi-solid which was carried on to the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([C:20](=[O:21])[NH:22][C:23]4[S:24][CH:25]=[CH:26][N:27]=4)[CH:28]=[CH:29][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[5-(thiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.99 min, MH+ 393. NMR: δH [2H6]-DMSO 12.71,(1H, b), 9.13,(1H, s), 8.86,(1H, t), 8.34,(1H, d), 8.21,(1H, s), 8.07,(1H, d), 7.81,(1H, d), 7.57, (1H, d), 7.52,(1H, d), 7.29,(1H, d), 3.21,(2H, t), 2.45,(3H, s), 1.07,(1H, m), 0.47, (2H, m), 0.27,(2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:28])[N:19]([C@H:23]5[CH2:27][CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.[CH2:35]=O>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:28])[N:19]([C@H:23]5[CH2:27][CH2:26][N:25]([CH3:35])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@H]1CCNC1
Product: CN1CC[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S)-1-methylpyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S)-pyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 114) and formaldehyde following General Procedure R.
Reaction SMILES: [CH2:1]([O:3][C:4](=[S:17])[NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH3:2].C[C:19](C)([O-:21])C.[Li+]>CN(C)C=O>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][N:5]1[CH2:2][C@H:1]([CH2:19][OH:21])[O:3][C:4]1=[S:17]
Reactant: CCOC(=S)NCCOc1ccccc1OC
Reactant: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccccc1OCCN1C[C@H](CO)OC1=S

Procedure:
Using N,N-dimethylformamide solution of ethyl-2-(2-methoxyphenoxy)ethylthiocarbamate 51.0 g (0.2 mol), lithium-t-butoxide 3.2 g (0.04 mol) and (R)-2-oxyranylmethoxy-tetrahydropyran 34.76 g (0.22 mol), the procedures as described in Example 1 were carried out to obtain the targeted product.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:12]([CH:13]2[C:21]3[C:16](=[C:17]([Cl:22])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]2([CH3:25])[CH3:24])[CH:11]=[N:10][CH:9]=1)(C)(C)C.Cl.C(OCC)C>CO.C([O-])(O)=O.[Na+]>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[C:15](=[O:23])[C:14]([CH3:25])([CH3:24])[CH:13]2[N:12]1[C:8]([CH2:7][OH:6])=[CH:9][N:10]=[CH:11]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncn1C1c2cccc(Cl)c2C(=O)C1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC1(C)C(=O)c2c(Cl)cccc2C1n1cncc1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-7-chloro-2,2-dimethyl-indan-1-one (650 mg, 1.6 mmol) in methanol (20 mL) is added a 1N solution of HCl in diethyl ether (15 mL, 15 mmol). The reaction is permitted to stir for 30 minutes, at which time the reaction is cooled to 0° C. and diluted with saturated aqueous NaHCO3. The reaction mixture is then concentrated in vacuo to ca. one fourth of the original volume and diluted with ethyl acetate. The layers are separated and the aqueous layer is extracted two times with ethyl acetate. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:19) to furnish 7-chloro-3-(5-hydroxymethyl-imidazol-1-yl)-2,2-dimethyl-indan-1-one; 1H NMR (400 MHz, CD3OD) δ ppm 0.86 (s, 3 H), 1.41 (s, 3 H), 4.77 (dd, 2 H); 5.88 (s, 1 H), 7.01 (s, 1 H), 7.09 (s, 1 H), 7.45 (d, J=7.58 Hz, 1 H), 7.62 (d, J=7.83 Hz, 1 H), 7.74 (t, J=7.71 Hz, 1 H); HRMS: (ESI) m/z 291.0898 [(M+H)+: Calcd for C15H16N2O2Cl: 291.0900].
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14].[CH3:17][C:18]1([CH3:51])[O:23][C:22]([NH:24][C:25]23[CH2:32][CH:31]4[CH2:33][C:27]([C:34]([NH2:36])=[O:35])([CH2:28][CH:29]2[CH2:30]4)[CH2:26]3)=[N:21][S:20](=[O:38])(=[O:37])[C@@H:19]1[C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1>CN(C=O)C>[CH3:17][C:18]1([CH3:51])[O:23][C:22]([NH:24][C:25]23[CH2:32][CH:31]4[CH2:33][C:27]([C:34]([NH2:36])=[O:35])([CH2:28][CH:29]2[CH2:30]4)[CH2:26]3)=[N:21][S:20](=[O:37])(=[O:38])[C@@H:19]1[C:39]1[CH:40]=[CH:41][C:42]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:47][CH2:46]2)=[CH:43][CH:44]=1
Reactant: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1c1ccc(C2CCNCC2)cc1
Reactant: FC(F)(F)CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1c1ccc(C2CCN(CCC(F)(F)F)CC2)cc1
Reaction time: 8 h

Procedure:
DIPEA (75 mg) and 3-bromo-1,1,1-trifluoropropane (500 mg) were added to a solution of 3a-[(R)-6,6-dimethyl-4,4-dioxo-5-(4-piperidin-4-yl-phenyl)-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-2-ylamino]hexahydro-2,5-methanopentalene-2-carboxamide (73 mg) in DMF (1.5 mL), and the mixture was stirred overnight. The resulting mixture was purified in a purification laboratory by means of preparative HPLC. This gave the product with a molecular weight of 596.7 g/mol (C29H39F3N4O4S); MS (ESI): m/e=597 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:14]=3)=[CH:11][C:10]([NH2:26])=[N:9]2)=[CH:4][CH:3]=1.[O:27]=[C:28]1[NH:32][CH2:31][C@@H:30]([C:33](O)=[O:34])[CH2:29]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:21][C:22]([F:24])([F:23])[F:25])[CH:14]=3)=[CH:11][C:10]([NH:26][C:33]([C@H:30]3[CH2:29][C:28](=[O:27])[NH:32][CH2:31]3)=[O:34])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: Nc1cc(-c2cccc(COCC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1C[C@H](C(=O)Nc2cc(-c3cccc(COCC(F)(F)F)c3)n(-c3ccc(F)cc3)n2)CN1
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (43 mg) in N,N-dimethylacetamide (0.4 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (17 mg) prepared according to the same procedures as Preparation 5 and WSC.HCl (34 mg) at room temperature, and the mixture was stirred for 0.5 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (26 mg).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]=1/[CH:19]=[CH:20]/C=O>O1CCCC1.CCCCCC>[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:8]1[O:7][C:1](=[O:6])[CH2:2][CH:3]([OH:4])[CH2:5]1
Reactant: O=C/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CC(O)CC(/C=C/c2c(Cl)cc(Cl)cc2OCc2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 107.5 %

Procedure:
Methyl acetoacetate (9.56 g, 82.3 mmole) was added dropwise to a stirred suspension of sodium hydride (50% oil suspension) (3.95 g, 82.3 mmole) in anhydrous tetrahydrofuran at 0° C. under a nitrogen atmosphere. The resulting solution was stirred 15 minutes at 0° C. and then treated with a 1.6M solution (51.5 ml, 82.3 mmole) of n-butyllithium in hexane over 5 minutes. The resulting yellow solution was stirred 15 minutes at 0° C. and then treated with a solution of (E)-2,4-dichloro-6-phenylmethoxycinnamaldehyde (25.3 g, 82.3 mmole) in anhydrous tetrahydrofuran (150 ml). The resulting orange solution was stirred 15 minutes at 0° C. and then quenched by dropwise addition of 12N hydrochloric acid (ca. 20 ml). The reaction mixture was diluted with water (100 ml) and extracted with ether (3×300 ml). The organic extracts were combined, washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo leaving the title compound as a yellow oil (34.8 g, 100%): pmr (CDCl3) δ2.75 (2H, d), 3.45 (2H, s), 3.72 (3H, s), 4.71 (H, m), 5.50 (2H, s), 7.37 (5H, s).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH:2]=[CH2:3].[N+:15]([CH3:18])([O-:17])=[O:16]>O>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])([CH2:18][N+:15]([O-:17])=[O:16])[C:5]1=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)C(=O)c2ccccc21
Reactant: C[N+](=O)[O-]
Solvent: O
Product: C=CCN1C(=O)C(O)(C[N+](=O)[O-])c2ccccc21
Temperature: 40 °C
Reaction time: 24 h

Procedure:
1-allylindoline-2,3-dione (0.093 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 40° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[CH:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:27]=[S:19]1(=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:28])=[O:5])[CH:9]=2)[NH:18]1
Reactant: CC(C)(C)OC(=O)Cn1cc(C2NS(=O)(=O)c3ccccc32)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1cc(C2NS(=O)(=O)c3ccccc32)c2ccccc21
Reaction time: 13 h

Procedure:
The product of example 1, step d (32 mg, 0.08 mmol) was treated with trifluoroacetic acid (TFA) (neat) or 70% TFA in DCM. After stirring 2-24 h, the reaction was concentrated to dryness and purified by preparative LCMS to give the title compound. 1H NMR (DMSO-d6) δ 7.90-7.86 (m, 1H), 7.66-7.57 (m, 2H), 7.38 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.25-7.20 (m, 2H), 7.06 (t, J=7.2 Hz, 1H), 6.87 (t, J=7.2 Hz, 1H), 6.07 (s, 1H), 4.62 (s, 2H); MS: ESI (negative): 341 (M−H).
Reaction SMILES: Cl.Cl.[OH:3][C@H:4]1[CH2:8][NH:7][C@H:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=CN=2)[CH2:5]1.[F-].[C:18]([N+:22](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1>[OH:3][C@H:4]1[CH2:8][NH:7][C@H:6]([CH2:9][O:10][C:11]2[CH:18]=[N:22][CH:14]=[CH:15][CH:16]=2)[CH2:5]1
Reactant: CC(C)(C)[N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C
Reactant: O[C@H]1CN[C@H](COc2ccccn2)C1
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@H]1CN[C@H](COc2cccnc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 1.35 g sample of the compound from step 72d above was dissolved in 9 mL of THF and 9.3 mL of tetra-(t-butyl)ammonium fluoride was added. The reaction mixture was stirred at room temperature for 16 hours, and the volatiles were removed under vacuum. The residue was purified on silica gel, eluting with 3:1 ethyl acetate:hexane, to give the title compound.
Reaction SMILES: [C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH2:30])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39].O>CN(C)C=O>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][CH2:6][CH2:7][N:8]([CH3:9])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCN(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CC(C)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CCCN(C)C)c1ccc(-c2cc(=O)c3c(NCCCC(C)C)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
1.01 g (2.33 mmol) of 2-[4-[N-acetyl-N-(3-dimethylaminopropyl) amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 127 (2) was dissolved in 20 mL of dimethylformamide under argon atmosphere, 190 mg (4.75 mmol) of sodium hydride (60% oil dispersion) and 0.66 mL (4.7 mmol) of 1-bromo-4-methylpentane were added under ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and mixture was extracted twice with ethyl acetate. The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1-9:1) to give 595 mg of 2-[4-[N-acetyl-N-(3-dimethylaminopropyl)amino]-3-fluorophenyl]-6,8-difluoro-5-(4-methylpentylamino)-4H-1-benzopyran-4-one (yield: 49%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([OH:21])=[C:16]([Br:22])[CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:21][S:24]([CH3:23])(=[O:26])=[O:25])=[C:16]([Br:22])[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1c(Br)ccc2cc(OCc3ccccc3)ccc12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Oc1c(Br)ccc2cc(OCc3ccccc3)ccc12
Yield: 80 %

Procedure:
Add sodium hydride (24 g, 0.6 mmol) portionwise to a solution of 6-benzyloxy-2-bromo-naphthalen-1-ol (179 g, 0.54 mol) in THF (3.0 L) at 0° C. Add methanesulfonyl chloride (47 mL, 0.61 mol) over 45 minutes and stir the reaction for 1.5 hours at 10° C. Add sodium bicarbonate solution (500 mL) and water (500 ml). Separate the layers and extract the aqueous layer with ethyl acetate (500 mL×2). Combine the organic layers and wash with brine (200 mL). Dry with magnesium sulfate, filter and concentrate in vacuo. Triturate the residue by adding 20% ethyl acetate in hexane (1 L) to obtain a solid. Filter, wash the solid with toluene (200 mL×2) and dry the solid to get 176 g (80%) of methanesulfonic acid 6-benzyloxy-2-bromo-naphthalen-1-yl ester.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[ClH:15]>O>[ClH:15].[NH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)[NH2:1]
Reactant: O=N[O-]
Reactant: N#CCc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(NN)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of sodium nitrite (4.0 g) in water (34 ml) was added dropwise at -5° to -2° to a suspension of 4-aminobenzeneacetonitrile (7.6 g) in concentrated hydrochloric acid (80 ml), and stirring was continued at -2° for 20 min. The mixture was filtered and the filtrate added dropwise at 0° to 5° to a solution of tin (II) chloride dihydrate (65 g) in concentrated hydrochloric acid (130 ml). The mixture was allowed to warm to room temperature overnight (17 h), and the precipitate was filtered off, washed with concentrated hydrochloric acid, cold absolute ethanol, and dry ER, and dried to give the title salt as a powder (6.05 g). m.p. 207°-210° (foams).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)[C:10]=2[F:33])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[F:33][C:10]1[C:11]([CH2:23][NH:24][CH3:25])=[CH:12][N:13]([S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:9]=1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C#N)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (433 mg) in ethanol (5 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 175 mg, 47%).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.[O:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>C(#N)C>[Br:8][C:6]1[N:7]=[C:2]2[N:29]([CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: NC1CCOCC1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CN(C2CCOCC2)c2nc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of N-(3,5-dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (6.6 g, 15.8 mmol) and diisopropylethylamine (4.0 g, 31.6 mmol) in acetonitrile (50 mL) was added tetrahydro-2H-pyran-4-amine (6.4 g, 63.2 mmol) and the mixture was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue which was purified by chromatography on silica gel (5-20% ethyl acetate in petroleum ether) to give the title compound (1.98 g, 40% yield). MS (ESI) m/z 313.1 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][NH:11][S:20]([C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[Cl:12])(=[O:22])=[O:21]
Reactant: CC1CC(C)N(CCCN)C1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: c1ccccc1
Product: CC1CC(C)N(CCCNS(=O)(=O)c2cc(Cl)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
2,4-Dimethyl-1-(3-aminopropyl) pyrrolidine in (4.7 g, 0.03 mol) benzene (30 ml) was added dropwise at room temperature to a solution of 2,5-dichlorobenzenesulphonylchloride (7.3 g, 0.03 ml) in benzene (100 ml). Thereafter, the mixture was stirred for 4 days at room temperature until the reaction was complete. Finally, the reaction product was obtained as a viscous, oily paste. The benzene mother liquor was decanted. The residue was dissolved in water, the solution was adjusted to pH 9.8 with 10% NaOH and extractes with petroleum ether (40°-60°) (4×100 ml). The combined extracts were dried over Na2SO4 and evaporated. The residue (5 g) was recrystallised twice from 100 ml petroleum ether to yield the product (3.7 g as white needles), m.p. 65°-67° C. Yield=67% of theoretical
Reaction SMILES: Cl[Si:2]([CH3:22])([CH3:21])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4]1.CCN(CC)CC.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31]>CCCCCC>[CH3:31][C:30]([NH:34][Si:2]([CH3:22])([CH3:21])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4]1)([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(Cl)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)N[Si](C)(C)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Reaction time: 24 h
Yield: 88.7 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-3-phenyl-s-indacen-1-yl)silane (10.8277 g, 0.03322 moles) was stirred in hexane (150 mL) as NEt3 (3.5123 g, 0.03471 moles) and t-butylamine (2.6074 g, 0.03565 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a thick red-yellow oil (10.6551 g, 88.7% yield).