Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:16])[CH:15]=1)=[O:8].[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[F:16][C:14]1[CH:15]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)[CH:3]=[CH:4][C:5]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=[N:12][CH:13]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1cncc(F)c1)c1cc(Br)ccc1OCc1ccccc1
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: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1cncc(F)c1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 130 °C

Procedure:
To a microwave vial was added 5-bromo-N-(5-fluoro-3-pyridinyl)-2-[(phenylmethyl)oxy]benzamide (may be prepared as described in Example 98; 200 mg, 0.50 mmol), 1,4-dioxane (2 ml), 4-pyridinylboronic acid (73.5 mg, 0.60 mmol), 1M sodium carbonate (1.00 ml, 1.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.6 mg, 0.03 mmol). The vial was sealed and heated to 130° C. for 30 min under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified using MDAP (twice) to yield the title compound. 9 mg.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH2:13])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:13][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)([CH3:5])[CH2:3][OH:2]
Reactant: COC(=O)C(C)(N)c1cccc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)(CO)c1cccc(Br)c1
Temperature: -7 °C
Reaction time: 0.5 h
Yield: 104.7 %

Procedure:
A solution of the (RS)-2-amino-2-(3-bromo-phenyl)-propionic acid methyl ester (9.39 g, 36 mmol) in tetrahydrofuran (360 ml) was treated portionwise at −5° C. with lithiumaluminiumhydride (1.41 g, 36 mmol; 282 mg/2 min). After complete addition, stirring was continued at 0-5° C. for 30 minutes. For the workup, the reaction mixture was cooled to −7° C., and water (9 ml) was added dropwise. Thereafter, 2 N sodium hydroxide solution (9 ml) was added and stirring continued for 15 minutes at room temperature. They grey suspension was filtrated through Dicalite which was washed with tetrahydrofuran (200 ml). The filtrate was evaporated at reduced pressure. There were obtained 8.67 g of crude (RS)-2-amino-2-(3-bromo-phenyl)-propan-1-ol as colorless oil. The purity of the product allowed using it in the next step without further purification. Mass (calculated) C9H12BrNO [230.106]; (found) [M+H]+=230, 232.
Reaction SMILES: C(=O)([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[N:13]=[CH:12]2)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([SH:8])=[CH:17][CH:16]=3)[CH:12]=[N:13]2)=[CH:23][CH:22]=1
Reactant: O=C(Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Fc1ccc(-n2ncc3cc(S)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To S-1-(4-Fluorophenyl)-1H-indazol-5-yl benzothioate (37d, 0.046 g, 0.13 mmol) in methanol (3 mL), potassium carbonate (0.011 mL, 0.20 mmol) was added and the mixture was stirred at rt for 2 hrs. water was than added, 1N HCl (2 ml) and extracted with EtOAc (2*20 ml), dried, evaporated and then purified on HPLC. The relevant fractions were collected freeze dried and analysed by LC/MS.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1)([CH3:3])[CH3:2].[Na+].Cl[CH2:14][C:15]([O-:17])=[O:16].[OH-].[K+]>O>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[O:11][CH2:14][C:15]([OH:17])=[O:16])([CH3:3])[CH3:2]
Reactant: O=C([O-])CCl
Reactant: Cc1cc(O)cc(C(C)C)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(OCC(=O)O)cc(C(C)C)c1
Yield: 62.9 %

Procedure:
3-Isopropyl-5-methylphenol (44.0 g, 0.29 mol) and chloroacetic acid sodium salt (35.0 g, 0.3 mol) was dissolved in 180 mL of H2O, and then KOH (86%, 20 g, 0.3 mol) was added slowly. The reaction mixture was refluxed overnight and thereafter concentrated by distillation. After cooling, the mixture was acidified to pH 1, and then extracted with EtOAc. The organic layer was washed H2O, dried over MgSO4, and concentrated. The solid was recrystalized in 5% isopropanol in hexane to give pure 3-isopropyl-5-methylphenoxyacetic acid (38 g, 63%) as white crystals.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[CH:19]/[C:20](O)=[O:21]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:20](=[O:21])/[CH:19]=[CH:18]/[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccccn1
Agent: Cl
Product: O=C(/C=C/c1ccccn1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-pyridyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 258 (MH+).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3:4].[OH:5][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7].Cl>>[O-:8][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:7])=[O:5].[Al+3:4].[O-:8][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:7])=[O:5].[O-:8][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:7])=[O:5]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Aluminum tris-triflate (CF3SO3)3Al is prepared by placing a premeasured amount of anhydrous aluminum trichloride (tribromide) in a well dried three necked flask equipped with a magnetic stirrer, a pressure equalizing dropping funnel and dry nitrogen inlet. The flask is cooled and 3 equivalents of triflic acid are slowly added from the dropping funnel with efficient stirring whereby HCl (HBr) slowly evolves. The temperature was slowly raised until completion of the reaction. The flask is then evacuated in vacuum to remove any HX and residual triflic acid giving aluminum triflate as a slightly off colored solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[C:9]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]2[C:15](=[O:27])[N:14]3[C:28]([CH3:31])=[N:29][N:30]=[C:13]3[N:12]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]=2[N:10]=1>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:16]3[C:15](=[O:27])[N:14]4[C:28]([CH3:31])=[N:29][N:30]=[C:13]4[N:12]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]=3[N:10]=[C:9]2[N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:20][CH:21]=1
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1c2nc(-n3cncn3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
Sodium hydride 60% in mineral oil (18 mg, 0.74 mmol) was added to a solution of 1H-1,2,4-Triazole (45 mg, 0.65 mmol) in DMF (10 mL) at room temperature. After stirring for 1 hour at room temperature, 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (200 mg, 0.40 mmol) in DMF was added to above solution and the mixture was stirred overnight. The reaction was quenched with a drop of water and the reaction mixture was purified by pre LC-MS to give the desired product (53 mg, 27.2%) and its region-isomer 6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1H-1,2,4-triazol-1-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (53 mg, 27%). LCMS calculated for C22H26N9O2 (M+H): 448.2. Found 448.2.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].O>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1cccnc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-3-pyridinol (5 g) in THF (100 ml) at 0° was added sodium hydride (1 g, 80% suspension in oil). The mixture was stirred under nitrogen for 30 min and methyl bromoacetate (3.26 ml) was added dropwise. The mixture was then heated under reflux for 2 h, poured into water (300 ml) and extracted with ethyl acetate (2×250 ml). The combined organic extracts were dried and concentrated to give a solid which was triturated with ether to give the title compound as a white solid (4.5 g), m.p. 63°-64° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:15]=2)[C:10]([CH:35]2[CH2:37][CH2:36]2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([CH:35]2[CH2:36][CH2:37]2)=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)c2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(C2CC2)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Tert-butyl6-(tert-butyldiphenylsilyloxy)-3-cyclopropylindazole-1-carboxylate (5.08 g) which can be prepared according to the method described in Reference example 6, etc. was dissolved in THF (53 mL; manufactured by Kanto Chemical Co., Inc.), and added with 1 mol/L-TBAF-THF solution (19.82 mL), followed by stirring at room temperature for 0.5 hours. To the reaction solution, water and brine were added and extraction was carried out three times with ethyl acetate. The organic layer was washed water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (2.54 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:16])[CH3:15])=[C:7](I)[CH:6]=1)=[O:4].[Br-].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([Zn+])=[N:24][CH:25]=1>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:16])[CH3:15])=[C:7]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(I)c2cnn(C(C)C)c2c1
Reactant: Cc1ccc([Zn+])nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(C)cn2)c2cnn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 4-iodo-1-isopropyl-1H-indazole-6-carboxylic acid methyl ester (1.13 g, 3.28 mmol) in THF (30 mL) was added Pd(PPh3)4 (0.2 g, 0.164 mmol), followed by 5-methyl-pyridinyl zinc bromide ((19.7 mL of 0.5M solution in THF, 9.86 mmol). The reaction mixture was stirred overnight at room temperature, then quenched by addition of saturated aqueous NH4Cl solution. The mixture was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography gave 0.5 g (50%) of 1-isopropyl-4-(5-methyl-pyridin-2-yl)-1H-indazole-6-carboxylic acid methyl ester.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])#[N:4]>C1(C)C=CC=CC=1>[NH2:4][C:3]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=1[C:10]#[N:11]
Reactant: N#CCCCCCC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1=C(N)CCCC1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To cold toluene (20 mL) was added 60% NaH (720 mg, 18.0 mmol) slowly and followed by a solution of 1,5-dicyanopentane (2.1 mL, 16.37 mmol) in toluene (5 mL) slowly at 0° C. The resulting mixture was refluxed for 4 h and cooled to room temperature. The reaction mixture was quenched with ethanol (2 mL), water (20 mL) and acetic acid (2 mL). The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Water was added to the crude residue, then filtered and washed with hexane to afford 850 mg (42%) of 2-aminocyclohex-1-enecarbonitrile (I-7a) as a pale brown solid.
Reaction SMILES: N[C@H](C(OC)=O)CC(OC)=O.[NH2:12][C@H:13]([C:20]([O:22]C)=[O:21])[CH2:14][CH2:15][C:16]([O:18]C)=[O:17]>>[NH2:12][C@H:13]([C:20]([OH:22])=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: COC(=O)C[C@H](N)C(=O)OC
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
In like manner, but using dimethyl aspartate and dimethyl glutamate in place of diethyl malonate affords the corresponding N-[3β-hydroxy-11-oxo-18β-olean-12-en-30-oyl]aspartic acid and glutamic acid compounds which are converted to their disodium salts according to Example I-C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[C:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[CH:2]1.[OH:19]O>CO>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[C:7]2[CH2:12][CH2:11][N+:10]([O-:19])([CH3:13])[CH2:9][CH2:8]2)=[CH:2]1
Reactant: OO
Reactant: CN1CCC(=C(c2ccsc2)c2ccsc2)CC1
Solvent: CO
Product: C[N+]1([O-])CCC(=C(c2ccsc2)c2ccsc2)CC1
Reaction time: 192 h
Yield: 77 %

Procedure:
5.5 grams (0.02 mole) of 4-(di-3-thienyl-methylene)-N-methyl-piperidine were dissolved in 50 ml of methanol and treated with 7.2 grams of 30% hydrogen peroxide dropwise with ice cooling and left at room temperature for 8 days. Excess hydrogen peroxide was destroyed by the addition of Pt-carbon. After the filtering and removal of the solvent at room temperature the amineoxide was crystallized in ethyl acetate. M.P. 92°-96° C.; Yield: 77%.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH3:22])[C:14]4=[O:23])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB(/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]>C(Cl)Cl>[F:57][C:56]([F:59])([F:58])[C:54]([OH:60])=[O:55].[CH3:22][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@:13]2([CH2:12][C@H:11]2[C:7]2[CH:6]=[C:5]3[C:10]([C:2](/[CH:32]=[CH:33]/[C:34]4[CH:35]=[CH:36][C:37]([N:40]5[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]5)=[CH:38][CH:39]=4)=[N:3][NH:4]3)=[CH:9][CH:8]=2)[C:14]1=[O:23]
Reactant: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)n[nH]c3c2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=C/B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(/C=C/c4ccc(N5CCNCC5)cc4)n[nH]c3c2)c2ccccc21
Reaction time: 2 h
Yield: 4 %

Procedure:
The title compound was synthesized according to the method of Example A45, except substituting (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (37 mg, 0.090 mmol) and (E)-tert-butyl 4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenyl)piperazine-1-carboxylate (45 mg, 0.109 mmol). The solvent was removed and the Boc-protected amine purified by column chromatography (silica gel, CH2Cl2/MeOH, 95:5) to give an impure product which dissolved into CH2Cl2 (2.0 mL) and TFA (200 uL) was added. The reaction was stirred for 2 h, the solvent removed and the residue purified by prep-HPLC to give the title compound as an off-white powder (2.0 mg, 4.0%); 1H NMR (400 MHz, CD3OD) δ 7.97 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.46-7.41 (m, 2H), 7.30 (d, J=17 Hz, 1H), 7.15 (t, J=7.2 Hz, 1H), 7.06-6.99 (m, 4H), 6.65 (t, J=8.0 Hz, 1H), 6.02 (d, J=7.7 Hz, 1H), 3.49-3.44 (m, 4H), 3.40-3.31 (m, 8H), 2.28-2.25 (m, 1H), 2.21-2.18 (m, 1H); MS ESI [M+H]+ 476.2, calcd for [C30H29N5O+H]+ 476.25.
Reaction SMILES: [C:1]([NH:18][C:19]1[CH:20]=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:22]([CH3:24])[CH:23]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([NH:18][C:19]1[CH:20]=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:22]([CH3:24])[CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)OCC)n(C)c1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1cc(C(=O)OCC)n(C)c1

Procedure:
A solution of 1.0 g. of ethyl 4-hexadecanamido-1-methyl-2-pyrrolecarboxylate in 10 ml. of dry tetrahydrofuran is added dropwise to a solution of 6 ml. of 1 M borane in tetrahydrofuran under nitrogen and the pale yellow solution is heated to reflux overnight. After cooling and acidification with 1 N aqueous hydrochloric acid followed by neutralization with saturated sodium bicarbonate solution, the solution is extracted with ether. The extract is dried over anhydrous magnesium sulfate and evaporated. The residue is recrystallized from hexane to yield the product as a white solid.
Reaction SMILES: ClC(OC(Cl)C)=O.C[N:9]1[CH2:31][C:14]2=[C:15]3[C:19](=[CH:20][CH:21]=[C:13]2[O:12][CH2:11][CH2:10]1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH:17]=[CH:16]3.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.Cl.C(OCC)C>C(Cl)Cl>[C:25]1([S:22]([N:18]2[C:19]3[C:15](=[C:14]4[CH2:31][NH:9][CH2:10][CH2:11][O:12][C:13]4=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 43 °C
Reaction time: 1 h
Yield: 7.6 %

Procedure:
1-Chloroethyl chloroformate (1.0 mL, 7.0 mmol) was added to a solution of 2-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Example 5, 0.15 g, 0.44 mmol), and 1,8-bis-(dimethylamino)-naphthalene (proton sponge) (0.056 g, 0.26 mmol) in DCM (10 mL) and the mixture was stirred at 43° C. for 1 hour. 1.0 M HCl in diethylether (2.5 mL, 2.5 mmol) was added and the mixture was evaporated. The residue was dissolved in dry MeOH (10 mL) and heated at 78° C. for 30 minutes and evaporated. The residue was dissolved in DCM and washed with water, brine, and the organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using MeOH:DCM:NEt3 (5:94:1) as the eluent to give the title compound (11 mg) as a light pink solid. MS m/z 329 [M+H]+.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]([CH3:5])([CH3:4])[CH3:3].Br[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH2:21].O1CCCC1>[Cl-].[Zn+2].[Cl-]>[CH3:19][C:14]1([CH3:20])[CH2:13][CH:12]([NH2:21])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH:10]=2)[NH:15]1
Reactant: CC1(C)CC(N)c2cc(Br)ccc2N1
Reactant: CC(C)(C)C[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc2c(c1)C(N)CC(C)(C)N2
Reaction time: 0.17 h

Procedure:
To neopentylmagnesium chloride (1.65 ml, 1.65 mmol) was added zinc(II) chloride (2.19 ml, 1.10 mmol) dropwise—strong exotherm was observed. The resulting mixture stirred for 10 minutes. A solution of 6-bromo-2,2-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine (0.0700 g, 0.274 mmol) in tetrahydrofuran (1.37 ml, 0.274 mmol) was then added followed by palladium tetrakistriphenylphosphine (0.0317 g, 0.0274 mmol). The reaction vessel was sealed and heated to 65 deg C. The reaction mixture was stirred for 6 hours. The crude mixture was filtered through a plug of celite with EtOAc and concentrated in the presence of silica gel. The crude mixture was purified with the MPLC (100% DCM to 100% 90:10:1 DCM:MeOH:NH4OH) to provide the desired product. MS m/z: 230 (M−NH2).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:24]=[CH:23][C:14]([CH:15]=[C:16]4[S:20][C:19](=[S:21])[NH:18][C:17]4=[O:22])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[NH4+]>>[O:22]=[C:17]1[C:16](=[CH:15][C:14]2[CH:13]=[CH:12][C:11]([N:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)=[CH:24][CH:23]=2)[S:20][C:19](=[S:21])[NH:18]1
Reactant: O=C1NC(=S)SC1=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: O=C1CCN(c2ccc(C=C3SC(=S)NC3=O)cc2)CC1
Yield: 89.2 %

Procedure:
5-[4(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-thioxothiazolidin-4-one (which was obtained in Example 33) (0.9 g, 2.5 mmol) was treated with concentrated hydrochloric acid (25 mL) at room temperature. After 15 hours ˜28% ammonium hydroxide (NH4OH) was added dropwise and the precipitate was collected by filtration, and dried over phosphorus pentoxide (P2O5) to give the title compound as a red solid (0.71 g, 89%); 1H NMR (300 MHz, DMSO-d6) δ 2.46 (t, J=6.1 Hz, 4H), 3.79 (t, J=6.1 Hz, 4H), 7.11 (d, J=9.0 Hz, 2H), 7.48 (d, J=9.0 Hz, 2H), 7.56 (s, 1H); MS (ES) m/z: 316.9 (M−H)−; HRMS Calcd. C15H14N2O2S2 (M+): 318.0497. Found: 318.0502.