Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:50][CH:49]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 90.5 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Degassed N,N-dimethylformamide (0.37 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 35.3 mg, 0.0582 mmol), 4-bromo-phenyl-acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 18.6 mg, 0.812 mmol), tetrakis(triphenylphosphine)palladium (0) (9.1 mg, 0.0079 mmol) and potassium phosphate (26.9 mg, 0.127 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 87 to 94° C. for three hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=50/1) to give the title compound (31.5 mg, 86%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][CH2:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:6])[CH3:5])[CH2:20][CH2:21]1
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Reactant: C1COCCN1
Product: CC(O)(CCN1CCOCC1)c1ccccc1-c1ccccc1

Procedure:
2.6 g of 1-chloro-3-p-biphenylyl-butan-3-ol are boiled with 30 ml of morpholine for 1.5 hours and the mixture is cooled and worked up in the customary manner to give 1-morpholino-3-p-biphenylyl-butan-3-ol, m.p. 116°-118°.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+].C(Cl)(Cl)Cl>Cl.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(OCCn2ccnc2)cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ccc(OCCn2ccnc2)cc1
Yield: 69.8 %

Procedure:
Iron powder (6.0 g) was added in portions to a warm solution of 1-[2-(4-nitrophenoxy)ethyl]imidazole (3.7 g) in 5N hydrochloric acid (60 ml). After 20 minutes the solution was cooled, made basic with dilute sodium hydroxide solution and the mixture was shaken with chloroform and filtered. The chloroform layer of the filtrate was separated, dried (Na2SO4) and evaporated to give a solid which was crystallised from ethyl acetate/petrol to give 1-[2-(4-aminophenoxy)ethyl]imidazole (2.25 g) m.p. 91°-92° C. Found: C, 64.35; H, 6.40; N, 20.61. C11H13N3O requires: C, 65.01; H, 6.45; N, 20.68%.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:23]Br>ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>[Br:23][C:13]1[CH:14]=[C:9]2[CH2:8][CH2:7][N:6]([Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:16])[CH3:15])[C:10]2=[N:11][CH:12]=1
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cccnc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a 0° C. solution of 1-(tert-butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (20 g, 85.6 mmol) and pyridine (8.4 mL) in dichloromethane (500 mL) was added dropwise to a solution of bromine (5.6 mL, 111.4 mmol) in dichloromethane (400 mL) over a period of 1 h. After stirring for 1 h at 0° C., the mixture was diluted with a mixture of saturated solutions of sodium thiosulfate-sodium bicarbonate (1:1 v/v) and stirred vigorously for 30 min. The resulting mixture was partitioned and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 2% ethyl acetate/hexanes) to afford 5-bromo-1-(tert-butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (22.5 g, 84%) as a light yellow oil: LC/MS m/e calcd for C13H22BrN2Si [M+H]+ 314.32, observed 313.1, 315.1; 1H NMR (400 MHz, CDCl3) δ ppm 0.32 (s, 6H), 0.96 (s, 9H, 3×CH3), 3.01 (t, J=8.7 Hz, 2H), 3.68 (t, J=8.7 Hz, 2H), 7.21 (br. s., 1H), 7.81 (br. s., 1H).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:21]O>>[NH2:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=1)[CH2:3][C:4]([O:6][CH3:21])=[O:5]
Reactant: NC(CC(=O)O)c1ccc2c(c1)OCCO2
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Amino-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propionic acid [synthesis according to instructions known from the literature (e.g., L. Lázár, T. Martinek, G. Bernáth, F. Fülöp, Synth. Comm. 1998, 28, 219-224)]is introduced into a vessel in methanol (about 0.5 to 1.0 mol/l) and admixed dropwise at 0° C. with 1.2 eq of thionyl chloride. When the addition has been made the reaction mixture is stirred at room temperature overnight and subsequently concentrated. The residue is dissolved in a little methanol and the product is precipitated with diethyl ether. The solid is filtered off with suction, washed repeatedly with diethyl ether and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10]([OH:18])(=O)[C:11]1[CH:16]=[CH:15]C=NC=1.O1C=CCC1>CN(C)C=O>[O:18]1[CH2:10][CH2:11][CH2:16][CH:15]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(O)c1cccnc1
Agent: C1=COCC1
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Temperature: 140 °C
Yield: 462.5 %

Procedure:
In 30 ml of dimethylformamide were dissolved 2.6 g of 5-fluorouracil and 0.246 g of nicotinic acid. 2.8 Grams of 2,3-dihydrofuran in several portions were added in 4 hours to the solution while heating it at 140° C. The mixture was then reacted for 4 hours at the same temperature. After completion of the reaction, dimethylformamide was distilled off from the reaction liquid and 50 ml of chloroform were added to the residue. After stirring, the solution was filtered to remove insoluble matters and the filrate was washed with water and dried over anhydrous sodium sulfate. Then, chloroform was distilled off from the dried filtrate to obtain 1.85 g of 1-(2-tetrahydrofuryl)-5-fluorouracil which had a melting point of 165°-168° C. The chloroform insoluble matters were 5-fluorouracil containing 0.24 g of nicotinic acid. The yield of the end product was 61% based on the consumed 5-fluorouracil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[N:7]([CH3:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1>>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[O:31])[CH2:30][CH2:29]2)=[O:12])[N:7]([CH3:13])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)O
Agent: Cl
Product: Cn1nc(C(C)(C)C)cc1C(=O)N1CCN(CC(=O)c2ccc(F)cc2)CC1
Yield: 91.9 %

Procedure:
The title compound was prepared in a similar manner as described in Example 1.2, using 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylic acid (27.3 mg), and 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg) as starting materials, to afford the title compound (35.5 mg) as a yellow solid. Exact mass calculated for C21H27FN4O2: 386.2. Found: LCMS m/z=387.5 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[F:11])=[N+]=[N-]>[Pt]>[F:11][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCc1ccncc1F
Agent: [Pt]
Product: NCc1ccncc1F

Procedure:
The product of Example 129C was processed according to the method of Example 115B except that Pt/C was used instead of Pd/C as catalyst. MS (ESI+) m/z 127 (M+H)+;
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[NH:8][C:9](=O)[N:10]([CH3:12])[CH3:11])#[N:2].P(Br)(Br)([Br:19])=O.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[N:8]=[C:9]([Br:19])[N:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CC(C)c1nsc(NC(=O)N(C)C)c1C#N
Reactant: O=P(Br)(Br)Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1nsc(N=C(Br)N(C)C)c1C#N
Yield: 47.9 %

Procedure:
To a solution of 22.8 g of N'-(4-cyano-3-isopropyl- 5-isothiazolyl)-N,N-dimethylurea in 300 ml of benzene was added 83.3 g of phosphorous oxybromide. The solution was cooled to 0° and 14 ml (9.7 g) of triethylamine was added. The ice-bath was removed and the reaction mixture was heated under reflux overnight. The following day the reaction mixture was filtered through sintered glass. The filtrate was washed with two 200 ml portions of cold water and two 200 ml portions of saturated sodium bicarbonate solution. Two hundred milliliters of chloroform was added to aid in separation of the organic phase from the final wash. The separated organic phase was dried, then concentrated under reduced pressure. The residue was passed over a column of 300 grams of silica gel with chloroform as the eluant. The first ten 250 ml fractions were evaporated to produce a yellow solid, mp 93°-97°. The combined residues were recrystallized from 175 ml of cyclohexane to yield 13.8 g of N'-(4 -cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylbromoformamidine mp 92°-96°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Li+].[CH3:15][CH:16]([N-]C(C)C)C.C(I)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:15][CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCOC(=O)C(CC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of ethyl 2-(4-bromophenyl)acetate (972 mg, 4 mmol) in 10 mL dry THF at −78° C. was added LDA (2 M, 2 mL, 4 mmol). The solution was warmed to rt and stirred 2 h, then was recooled to −78° C. EtI (0.52 mL) was added, then the reaction was stirred rt for 16 h. The reaction was quenched with sat. NH4Cl, then extracted with EtOAc (3×20 mL). The organic layer washed with brine, then dried (Na2SO4). Purification via flash chromatography (0-20% EtOAc in hexanes) gives 75A (228 mg, 21%). MS (ESI) m/z 271.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([OH:13])=O)=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.CN(C(O[N:38]1[N:46]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.O.NN>C(OCC)(=O)C.CN(C)C=O>[CH3:1][N:2]1[C:10]([C:11]([NH:38][NH2:46])=[O:13])=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:18][CH2:19]1
Reactant: Cn1c(C(=O)O)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(=O)NN)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Reaction time: 1 h
Yield: 41.5 %

Procedure:
In a 10 mL round bottomed flask, 9-Methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid (250 mg, 0.68 mmol, 1 equiv) and HATU (390 mg, 1.03 mmol, 1.5 equiv) were suspended anhydrous dimethylformamide (3 mL). Diisopropylethylamine (235 μL, 1.35 mmol, 2 equiv) followed by hydrazine monohydrate (330 μL, 6.81 mmol, 10 equiv) were added and the reaction stirred for one hour. The reaction mixture was diluted with ethyl acetate (20 mL), and the extracted with water (10 mL). The combined aqueous layer was then acidified with 1N aqueous hydrochloric acid to precipitate the desired product. This precipitate was filtered off, washed with water (2 mL) and acetonitrile (1 mL) and air dried yielding 115 mg of 9-methyl-6-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-9H-purine-8-carbohydrazide, which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][N:8]1[C:14](=[O:15])C[CH2:12][N:11]([C:16](=[O:39])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]3=4)=[O:26])=[CH:21][C:20]=2[CH3:38])[C:10]2[C:40](F)=[CH:41][CH:42]=[CH:43][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)CN1C2C(=C([Cl:63])C=CC=2)NCC1=O)(C)(C)C.C(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.NCC1C=CC(C(N2CCCCC3C=CC=CC2=3)=O)=CC=1C>>[C:1]([O:5][C:6](=[O:45])[CH2:7][N:8]1[C:9]2[C:10](=[C:40]([Cl:63])[CH:41]=[CH:42][CH:43]=2)[N:11]([C:16](=[O:39])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]3=4)=[O:26])=[CH:21][C:20]=2[CH3:38])[CH2:12][C:14]1=[O:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1C(=O)CNc2c(Cl)cccc21
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(F)c21
Agent: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CN
Agent: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC(=O)OC(C)(C)C)c2cccc(Cl)c21

Procedure:
Following the same procedure as described for 1D, (5-chloro-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl)acetic acid tert-butyl ester from Example 12E (450 mg, 1.5 mmol) was treated with phosgene (2.0 mmol) and diisopropylethylamine (2.0 mmol) followed by (4-aminomethyl-3-methylphenyl)-(2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)methanone from Example F (450 mg, 1.5 mmol) and diisopropylethylamine (2.0 mmol). The product was purified by flash chromatography on silica (eluant pet.ether:EtOAC, 100:0 to 50:50) to give a pale red solid; yield 510 mg, 54%.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([C:13]2[C:14]([CH3:25])=[N:15][O:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:21]3[CH:22]=[CH:23][C:18]([C:17]4[O:16][N:15]=[C:14]([CH3:25])[C:13]=4[C:10]4[O:9][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:12][N:11]=4)=[CH:19][CH:20]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1-c1nnc(Cc2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4-c4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 2-benzyl-5-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1,3,4]oxadiazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14]O)=[C:11]([CH3:16])[CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.S(Cl)([Cl:28])=O>C(Cl)Cl>[Cl:28][CH2:14][C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][C:11]=1[CH3:16]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reaction time: 8 h

Procedure:
To a solution of 62.6 (63 mg, 0.23 mmol) in DCM (2.3 mL) were added triethylamine (32 μL, 0.23 mmol) and thionyl chloride (25 μL, 0.35 mmol) at room temperature. The mixture was stirred overnight and concentrated to afford 62.7. The crude product was used without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:11]O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Ni]>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: ON=C1CCC2(CC1)OCCO2
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: NC1CCC2(CC1)OCCO2
Yield: 91.4 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one oxime (68 g, 400 mmol) in ethanol (200 mL) was added Raney Nickel as a suspension in ethanol (52 mL). The resulting mixture was shaken at 50 psi of hydrogen for 18 hours. The reaction was filtered and concentrated in vacuo to give 57.5g of 1,4-dioxaspiro[4.5]dec-8-ylamine.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]Br>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH3:2]
Reactant: BrCCCCBr
Reactant: COCCOCCO
Agent: [Na]
Product: COCCOCCOCCCCBr

Procedure:
This compound is prepared in a way similar to that in paragraph 1/ of example 1) by reacting the sodium salt of diethylene glycol monomethyl ether with an excess of 1,4-dibromobutane. Column purification gives a yellow-colored oil.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]2[NH:28][C:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[N:36](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:35]=[C:34]3[C:59]2[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=2)=[O:30])[CH:12]=[CH:13][CH:14]=1>C([SiH](CC)CC)C>[F:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:28][C:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][N:35]=[C:34]3[C:59]2[CH:60]=[CH:61][N:62]=[CH:63][CH:64]=2)=[O:30])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CNCCC1c1cccc(F)c1)c1ccc2[nH]nc(-c3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (1 mL) was added to tert-butyl 4-(3-fluorophenyl)-3-(3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxamido)piperidine-1-carboxylate (0.105 mmol). The reaction was stirred at room temperature for 30 minutes. Triethylsilane (1 drop) was added to the reaction and stirred for an additional 5 minutes. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:60])=[C:48]([NH:53][C:54](=[O:59])[O:55][CH2:56][CH:57]=[CH2:58])[CH:49]=[CH:50][C:51]=2[F:52])=O)[CH:40]=[CH:39][N:38]=1.C1C(=O)N(Br)C(=O)C1.[N:69]1([C:75](=[S:77])[NH2:76])[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:77][C:75]([N:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)=[N:76][C:44]=2[C:46]2[C:47]([F:60])=[C:48]([NH:53][C:54](=[O:59])[O:55][CH2:56][CH:57]=[CH2:58])[CH:49]=[CH:50][C:51]=2[F:52])[CH:40]=[CH:39][N:38]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: NC(=S)N1CCOCC1
Agent: O=C1CCC(=O)N1Br
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: C=CCOC(=O)Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate (4.0 g, 10.88 mmol), NBS (2.033 g, 11.42 mmol) and 4-morpholinecarbothioamide (1.749 g, 11.97 mmol) the title compound of Step F was obtained as a yellow solid (5.11 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (br. s., 1H), 8.41-8.51 (m, 1H), 7.83 (d, J=5.9 Hz, 1H), 7.27 (t, J=8.7 Hz, 1H), 6.76 (d, J=5.3 Hz, 1H), 5.88-6.03 (m, 1H), 5.34 (d, J=17.2 Hz, 1H), 5.22 (d, J=10.1 Hz, 1H), 4.61 (d, J=5.1 Hz, 2H), 3.70-3.76 (m, 4H), 3.57 (d, J=4.4 Hz, 4H). MS (ESI): 493 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:32])[C:17]2[N:22]=[C:21]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[CH:24]3)[CH:20]=[CH:19][N:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.Br>C(Cl)Cl.C(O)(=O)C>[NH:11]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:32])[C:17]2[N:22]=[C:21]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[CH:24]3)[CH:20]=[CH:19][N:18]=2)[CH2:12]1
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCN(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a 0° C. solution of 150 mg of 2-[(1-(benzyloxycarbonyl)-pyrrolidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (from EXAMPLE 11, step C) in 3 mL of CH2Cl2 was added 1 mL of 30% HBr in acetic acid. The cooling bath was removed after 5 min and the mixture was stirred at room temperature for 1 h, then diluted with 20 mL of water and extracted with 2×5 mL of CH2Cl2. The pH of the aqueous phase was adjusted to 11 with 5 N NaOH, and the aqueous phase was extracted with 5×10 mL of EtOAc, with continuous monitoring of the pH. The combined EtOAc extracts were dried over MgSO4 and concentrated to yield 40 mg of the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.62 (s, 1H), 8.38 (br s, 1H) 8.18 (d, J=7.6 Hz, 1H), 7.85 (dd, J=1.8, 7.1 Hz, 1H), 7.33-7.42 (m, 2H), 6.79 (d, J=5.5 Hz, 1H), 3.52 (t, J=6.4 Hz, 2H), 3.03-3.16 (m, 2H), 2.71-3.00 (m, 1H), 2.79 (dd, J=5.7, 11.0 Hz, 1H), 2.46-2.37 (m, 1H), 1.96-2.20 (m, 1H), 1.52-1.60 (m, 1H).