Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(N(CC)CC)C.Cl.[Cl-].[Na+]>CO.C(Cl)Cl>[F:9][C:2]([F:1])([F:8])[C:3]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:5]
Reactant: NCCCCCC(=O)O
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=C(O)CCCCCNC(=O)C(F)(F)F
Yield: 57.3 %

Procedure:
Ethyl trifluoroacetate (7.1 g, 50 mmole) is added with stirring to a suspension of 6-aminocaproic acid (I, 5.0 g, 40 mmole) in methanol (25 ml) and triethylamine (40 mmole) is added, with stirring. After stirring for 12 hours, by which time all the acid is in solution, the mixture is diluted with methylene chloride (100 ml) and made acidic (pH 1) with 1 N HCl. Saturated sodium chloride solution (90 ml) is then added and the lower layer is separated. The aqueous layer is extracted with methylene chloride (100 ml) and the two organic extracts are combined, dried over sodium sulfate and the solvents evaporated to afford 5.21 g of the desired acid II (Scheme I).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[C:7]2[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[N:8]=[C:7]2[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)CCOCn1nc(Sc2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(Sc2ccccc2)c2cc(N)ccc21
Yield: 89.2 %

Procedure:
5-Amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: a solution of 0.4 g of 5-nitro-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in 16 ml of ethyl acetate containing 40 mg of 10% palladium-on-charcoal is hydrogenated under a pressure of 200 kPa at a temperature in the region of 25° C. for 18 hours. After filtration of the catalyst through Celite® under argon and washing with ethyl acetate, the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. 0.33 g of crude 5-amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of a burgundy-colored oil. A second attempt using 1.1 g of 5-nitro-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole makes it possible to obtain, in the same way, 0.99 g of crude 5-amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in the form of a burgundy-colored oil. The two crude products are pooled and purified by chromatography under argon pressure (50 kPa), on a column of 53 g of silica (particle size 40-63 μm), eluting successively with pure cyclohexane then with cyclohexane/ethyl acetate (97/3; 95/5; 90/10; 80/20 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. 0.78 g of 5-amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of a burgundy-colored oil (El mass analysis: m/z 371 (M+) (base peak)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:26]=[C:27]=[O:28])[CH:24]=[CH2:25].O>CN(C)C=O>[CH2:23]([NH:26][C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:28])[CH:24]=[CH2:25]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: C=CCN=C=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in N,N-dimethylformamide (5 ml), allyl isocyanate (0.2 ml) was added, and the admixture was stirred at 80° C. for 15 hours with heat. Water was added to the reaction mixture, the admixture was extracted 2 times with ethyl acetate, and the organic layer was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 61 mg of the title compound (yield: 96%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C1=C(c2cccnc2)CCCC1
Yield: 90.9 %

Procedure:
A solution of 3-bromopyridine (0.38 g, 2.40 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol) and cesium carbonate (1.72 g, 5.29 mmol) in 1,4-dioxane (8.0 mL) and water (4.0 mL) was stirred at 90° C. for 4 hours. After allowing to cool, the reaction solution was subjected to extraction with ethyl acetate (50 mL), and the organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (hexane/ethyl acetate=2:1) to yield the title compound (347.3 mg, 99%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28](=[O:36])[C:29]4[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:37][N:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O)[CH3:39]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]([C:29]4[CH:30]=[C:31]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[CH2:40][N:38]([CH3:39])[CH3:37])[CH:32]=[CH:33][CH:34]=4)=[O:36])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CN(C)Cc1ccccc1B(O)O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)c4cccc(Br)c4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)c4cccc(-c5ccccc5CN(C)C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-benzoylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-(N,N-dimethylaminomethyl)-phenylboronic acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2=[N:18]O)[CH2:2][CH2:3][CH3:4]>CO.C1COCC1.N.[Ni]>[NH2:18][CH:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=2)[O:12][C:11]([CH3:16])([CH3:17])[CH2:10]1
Reactant: CCCCOc1ccc2c(c1)C(=NO)CC(C)(C)O2
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc2c(c1)C(N)CC(C)(C)O2
Yield: 72.2 %

Procedure:
A solution of 30 g of 6-butoxy-2,2-dimethylchroman-4-one oxime in 500 ml of methanol, 500 ml of THF and 30 ml of ammonia solution was hydrogenated in a shaking duck for 8 h in the presence of Raney nickel. After filtering off the catalyst and concentrating in vacuo, 20.5 g of 4-amino-6-butoxy-2,2-dimethylchroman were obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:7][CH2:8][CH:9]([OH:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1>CN(C)P(N(C)C)(N(C)C)=O>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][O:16][CH:9]([CH2:8][O:7][C:6]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:4]([Cl:3])[CH:5]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: OC(COc1ccc(Cl)c(Cl)c1)Cn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Clc1ccc(COC(COc2ccc(Cl)c(Cl)c2)Cn2ccnc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 56% dispersion of sodium hydride in mineral oil (240 mg.) is added under nitrogen to a solution of 1.43 g. of 1-[3'-(3",4"-dichlorophenoxy)-2'-hydroxypropyl]imidazole in 4 ml. of dry hexamethylphosphoramide. The reaction mixture is then stirred for 1 hour at 25° C., and then 1 hour at 45° C. The solution is then cooled in an ice bath and 1.07 g. of α,3,4-trichlorotoluene in 1 ml. hexamethylphosphoramide is added dropwise with stirring. The reaction mixture is then stirred for 1 hour at 5° C., and then for 1 hour at 25° C., and finally for 2 hours at 45° C. The mixture is then poured into 100 ml. of water and the resultant aqueous mixture extracted with ether and the ether extracts washed with water. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue is chromatographed on silica gel and eluted with 30% acetone in dichloromethane to yield pure 1-[2'-(3",4"-dichlorobenzyloxy)-3'-(3",4"-dichlorophenoxy)propyl]imidazole which is taken up in ether and treated with nitric acid yielding, after recrystallization of the crude salt from ethyl acetate/ether, 1-[2'-(3",4"-dichlorobenzyloxy)-3'-(3",4"-dichlorophenoxy)propyl]imidazole nitrate, m.p. 116°-118.5° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:5]=2[N:4]=1.S(=O)(=O)(O)O.[CH3:20]O>>[Cl:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:20])=[O:13])=[CH:11][C:5]=2[N:4]=1
Reactant: O=C(O)c1ccc2[nH]c(CCl)nc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2[nH]c(CCl)nc2c1
Yield: 71 %

Procedure:
To 2-(Chloromethyl)-1H-benzimidazole-5-carboxylic acid (4) (0.5 g; 2.4 mmole) suspended in anhydrous methanol (20 ml) was added dropwise Sulfuric acid (0.2 ml). The reaction mixture was maintained at reflux for 16 hours. The solvent was evaporated to give the crude oily product, which was purified by column chromatography (silica, 10% methanol: dichloromethane) to obtain 0.4 g (71% yield) of product 5.
Reaction SMILES: [C:1]1([C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[C:14]([C:24]#[N:25])=[C:13]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C[O:37]CC1>>[C:1]1([C:11]2[C:23]3[C:22](=[O:37])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[C:14]([C:24]#[N:25])=[C:13]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccc3ccccc23)c2c1-c1ccccc1C2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2cccc3ccccc23)c2c1-c1ccccc1C2=O
Temperature: 2.5 °C

Procedure:
A solution of 1-(naphthalen-1-yl)-3-(piperidin-1-yl)-9H-fluorene-4-carbonitrile (400 mg) in THF was added sodium hydride (39 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; mp 180-182° C.; ESIMS 415 (M-+1); IR (KBr) 2213 (CN), 1707 cm−1 (CO); 13C NMR (75.53 MHz, CDCl3): δ 22.65, 24.68, 51.57, 95.45, 115.96, 118.89, 121.27, 122.49, 122.80, 123.78, 123.92, 124.68, 124.78, 125.04, 127.22, 127.57, 129.35, 130.02, 132.05, 133.10, 133.93, 134.13, 139.41, 143.51, 149.06, 158.86, 187.99.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:36]=[CH:35][N:34](C(OC(C)(C)C)=O)[CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[CH:36]=[CH:35][NH:34][CH:33]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1ccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cc[nH]c3)c(C)sc2n1
Temperature: 100 °C
Yield: 20.4 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (100 mg, 0.232 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (1 mL). 1,1-Dimethylethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (102 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 100° C. for 10 min. The solution was then concentrated, ethyl acetate (10 mL) added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane and then further purified by MDAP (acidic conditions), to give the title compound (19.8 mg). LCMS (A) m/z: 416 [M−1]−, Rt 1.47 min (acidic).
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33](F)(F)F)[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.[NH2:39]C1C=C(C)C=C(C)N=1>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:39]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Product: Cc1cc(C)nc(NC(=O)c2ccc(C)c(NC(=O)c3cccc4c(N)nccc34)c2)c1
Yield: 8 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 and Step (4) of Example 1 were repeated step by step, except for using 2-amino-4,6-dimethylpyridine instead of aniline in Step (1) of Example 2 to obtain the title compound (2.8 mg, 8%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][NH:21][CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1.[C:31]1(=O)[CH2:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(C(C)C)C(C)C)C>ClCCCl.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][N:21]([CH:31]5[CH2:34][CH2:33][CH2:32]5)[CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: O=C1CCC1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4nsc5ccccc54)CC3)n1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)CN(C1CCC1)Cc1nnc([C@H]3CC[C@H](c4nsc5ccccc54)CC3)n1-2
Reaction time: 1 h

Procedure:
A solution of trans-1-(4-benzo[d]isothiazol-3-yl-cyclohexyl)-8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (35.0 mg, 0.0803 mmol), cyclobutanone (11.3 mg, 0.161 mmol) and acetic acid (0.009 ml, 0.2 mmol) in 1,2-dichloroethane (0.8 ml) was stirred at room temperature for 20 h. After addition of sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) the mixture was stirred for 1 h. Addition of methanol (0.5 ml) and N-ethyl diisopropylamine (0.028 ml, 0.16 mmol) to the reaction mixture was followed by concentration in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (27 mg, 69%) as white solid. MS m/e: 490 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[N:6]=[CH:5]2
Reactant: OB(O)c1cccnc1
Reactant: Brc1ccc2[nH]ncc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1ccc2c(cnn2-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.1 %

Procedure:
A mixture of 2.0 g (10.15 mmol) of 5-bromoindazole, 2.49 g (20.30 mmol) of 3-pyridyl boronic acid, 2.77 g (15.25 mmol) of copper acetate, and 2.4 mL of pyridine were dissolved in dry dichloromethane and stirred at room temperature. Oxygen gas was bubbled into the solution for 3 min and the mix was stirred in a screw top reaction vial in open atmosphere. After stirring overnight at room temperature, the reaction was monitored by LCMS which indicated ˜10-15% conversion. The mixture was then warmed to 70° C. After 24 hours, the mixture was cooled to room temperature, diluted with brine and extracted with EtOAc. The organic was washed with brine, dried over sodium sulfate, and concentrated in vacuo onto silica gel. The crude was then purified by Combiflash chromatography using a 0-70% EtOAc/hexanes gradient (product eluted at 35% EtOAc). The product containing fractions were combined and concentrated in vacuo to afford 0.31 g (11%) of 5-bromo-1-pyridin-3-yl-1H-indazole.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[CH:18]1([CH2:24]O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.COC(C)(C)C>[CH2:14]([O:13][C:11]([C:10]1[C:9]([CH3:16])=[N:8][N:7]2[C:2]([O:1][CH2:24][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:3][C:4]([CH3:17])=[CH:5][C:6]=12)=[O:12])[CH3:15]
Reactant: OCC1CCCCC1
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c(C)nn2c(OCC3CCCCC3)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 180 mg (0.768 mmol) of 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 8A in 7 ml of dry tetrahydrofuran was admixed with 0.189 ml (537 mmol) of cyclohexylmethanol, 423.2 mg (1.614 mmol) of triphenylphosphine and 0.32 ml (1.614 mmol) of diethyl azodicarboxylate. The resulting mixture was stirred at room temperature for 1 h. Some of the solvent was drawn off under reduced pressure and the residue was admixed with 5 ml of tert-butyl methyl ether. The resulting precipitate was filtered off and the mother liquor was partitioned between dichloromethane (15 ml) and water (10 ml). The organic phase was removed and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 220 mg (60% of theory, 71% pure) of the target compound.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[N:15]=[C:16]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([CH3:23])=[N:18]3)=[CH:7][C:8]=1[C:9]([O:11]C)=O)(=O)[CH3:2].O.[NH2:30][NH2:31]>C(O)C>[C:25]([NH:24][C:16]1[C:17]([CH3:23])=[N:18][C:19]2[C:14]([N:15]=1)=[C:13]([C:6]1[NH:5][C:4]3[C:1]([CH3:2])=[N:30][NH:31][C:9](=[O:11])[C:8]=3[CH:7]=1)[CH:22]=[CH:21][CH:20]=2)([CH3:27])([CH3:28])[CH3:26]
Reactant: NN
Reactant: COC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C(C)=O
Solvent: CCO
Solvent: O
Product: Cc1nc2cccc(-c3cc4c(=O)[nH]nc(C)c4[nH]3)c2nc1NC(C)(C)C
Temperature: 75 °C
Yield: 24.6 %

Procedure:
A mixture of methyl 2-acetyl-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (416b) (0.141 g, 0.37 mmol), hydrazine monohydrate (Fluka, 0.020 mL, 0.408 mmol) in Ethanol (1.23 mL) was heated to 75° C. for 24 h. Reaction mixture was directly loaded on silica gel samplet and purified by Biotage (30-100% EtOAc:EtOH (3:1)/hexanes) to produce 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-7-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (416) (33 mg, 0.091 mmol, 24% yield) that solidified as yellow solid upon drying. 1H NMR (300 MHz, MeOH) δ ppm 1.67 (s, 9H) 2.56-2.70 (m, 1H) 7.30-7.40 (m, 1H) 7.40-7.50 (m, 1H) 7.40-7.55 (m, 1H) 7.76-7.87 (m, 1H) 8.03-8.16 (m, 1H). m/z (ESI, +ve) 363.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:28](=[O:27])[C:23]5=[CH:22][C:21]([Cl:20])=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.63 g, 0.01 mole) and 4-chlorophthalic anhydride (1.82 g, 0.01 mole) in dichloromethane (100 ml) is stirred at room temperature for 3 hours. The solvent is removed under reduced pressure and the residual material is purified by flash chromatography. The product was purified further by recrystallization to give N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-chlorophthalimide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[CH:21][C:20]=1[CH3:27])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2)C=CC=1C(C1C=C(C#C[Si](C)(C)C)C=CC=1C)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]#[CH:26])[CH:22]=[CH:21][C:20]=1[CH3:27])=[O:18]
Reactant: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Agent: Cc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Product: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3)cc2Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 407, using compound 431 (5.95 mmol). The crude product was used without any further purification.