Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:37])[C:11]([NH:29]C(=O)OC(C)(C)C)=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCOCC1>[NH2:29][C:11]1[C:10](=[O:37])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]2[C:15](=[O:28])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:17][CH2:18][N:13]2[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60.7 %

Procedure:
To a solution of tert-butyl [9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazin-7-yl]carbamate (179 mg) in dioxane (2 ml) was added 4N hydrochloric acid/dioxane solution (2 ml) and the mixture was stirred at room temperature for 3.5 hr. The solvent was evaporated and aqueous sodium hydrogen carbonate solution was added to the obtained residue. The mixture was extracted with chloroform. The chloroform layer was dried, concentrated and purified by silica gel column chromatography (ethyl acetate:methanol=5:1) to give 7-amino-9-benzyloxy-2-(3-chloro-4-fluorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (88 mg).
Reaction SMILES: [O:1]([CH2:9][C:10]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:11][C:12](OC)=[O:13])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[O:17]([CH2:16][C:10]([CH2:9][O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:4])=[CH:11][CH2:12][OH:13])[Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19]
Reactant: COC(=O)C=C(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(=CCO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A solution of 5a (11.24 g, 30 mmol) in CH2Cl2 (100 mL) was cooled to -60° C. and treated dropwise with a solution of diisobutylaluminum hydride in CH2Cl2 (1.0M, 40 mL). The reaction mixture was quenched with saturated potassium sodium tartrate tetrahydrate and warmed to room temperature. The aqueous layer was extracted with CH2Cl2, and the combined organic layer was washed with water and brine. The organic layer was dried (NaSO4) and concentrated. The residue was purified by flash column chromatography over silica gel with hexane:EtOAc (5:1) as eluant to give 6a (9.77 g, 94%) as an oil: IR (neat) 3357, 1471 cm-1 ; 1H NMR (CDCl3) δ 0.05 and 0.06 (s, 6 H, SiCH3), 0.88 and 0.89 (s, 9 H, C(CH3)3), 1.86 (br s, 1 H, OH), 4.14 (br s, 2 H, CH2OH), 4.20 (m, 4 H, CH2OSi), 5.80 (m, 1 H, =CH); 13C NMR (CDCl3) δ -1.95, 18.19, 18.33, 25.62, 25.79, 25.88, 58.50, 59.24, 64.75, 125.47, 140.81. Anal. Calcd for C17H38O3Si2 : C, 58.90; H: 11.05. Found: C, 59.00; H, 11.00.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:17][CH:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.[Cl-].[NH4+]>C(#N)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:18]2[CH3:17])[C:7]=1[F:8]
Reactant: CC1CCCCCN1
Reactant: Fc1c(Cl)ncnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC1CCCCCN1c1ncnc(Cl)c1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 122.8 %

Procedure:
Into 2 ml of acetonitrile were added 0.13 g of 4,6-dichloro-5-fluoropyrimidine, 0.14 g of potassium carbonate and 0.10 g of 2-methylhexahydro-1H-azepine hydrochloride, and the mixture was stirred for 2 hours at 60° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 1-(6-chloro-5-fluoropyrimidin-4-yl)-2-methylhexahydro-1H-azepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]=O.C(O)(=O)C.[C-:15]#[N:16].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:15]#[N:16]
Reactant: [C-]#N
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: N#CCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5.25 parts of (2,6-dichlorophenyl)methanone, 4.08 parts of intermediate 8 and 105 parts of acetic acid was stirred for 2 hours at room temperature. There were added 1.96 parts of potassium cyanide and stirring was continued for 20 hours. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was washed with NaOH (10%) and water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /hexane 80:20). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 4.28 parts (49.3%) of (±)-α-[2-acetyl-5-ethylphenyl)amino]-2,6-dichlorobenzeneacetonitrile; mp. 111.3° C. (interm. 9).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:24]CCCCCC>>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:24]
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Reactant: CCCCCCCI
Product: CCCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21

Procedure:
Following a procedure similar to that used for the preparation of Intermediate 6a but using 1-iodo-n-heptane as the alkylating reagent the title compound was obtained as a colorless oil (66% yield).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7]([CH3:10])=[N:8][CH:9]=1.[C:12](Cl)(=[O:15])[O:13][CH3:14]>N1C=CC=CC=1>[CH3:14][O:13][C:12]([O:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7]([CH3:10])=[N:8][CH:9]=1)=[O:15]
Reactant: COC(=O)Cl
Reactant: Cc1ncc(CO)cc1O
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)OCc1cnc(C)c(O)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1.8 g. of 5-hydroxymethyl-2-methyl-3-pyridinol hydrochloride in 10 ml. of pyridine was added 1.0 g. of methyl chlorocarbonate dropwise under cooling. After standing overnight, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give 1.0 g. of an oily substance. The oily substance was purified by column chromatography (silica gel 20 g.) and 0.6 g. of the desired product as colorless crystal was obtained from the eluate with benzene-ethyl acetate (3:7) and recrystallized from ethyl acetate and n-hexane.
Reaction SMILES: C(S([N:7]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[C:8]1=[O:30])=O)(C)(C)C.[ClH:31]>CO.O1CCOCC1>[ClH:31].[ClH:31].[C:12]1([CH:11]2[CH2:10][C:9]3([CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[C:8](=[O:30])[NH:7]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(c1ccccc1)N(S(=O)C(C)(C)C)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1NC(c2ccccc2)CC12CCNCC2

Procedure:
To a solution of tert-butyl 2-(tert-butylsulfinyl)-1-oxo-3-phenyl-2,8-diazaspiro[4.5]decane-8-carboxylate (21 mg, 0.048 mmol) in methanol (4 mL) was added 4N HCl in dioxane (4 mL). After 24 h the reaction was concentrated give the title compound). MS: m/z=231.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.I[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13]([CH:21]([CH3:23])[CH3:22])[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:21]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:12]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cccnc1
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: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccnc2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of 3-Pyridinylboronic acid (15 mg, 0.14 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (15 mg, 0.015 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA52. ESI-MS (M+H)+ m/z calcd 255.1, found 255.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18].C(N(CC)CC)C>C(C(C)=O)C>[Cl:13][CH2:14][CH2:15][NH:16][C:17](=[O:18])[O:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: O=C=NCCCl
Reactant: Oc1ccc(Cl)c2cccnc12
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: O=C(NCCCl)Oc1ccc(Cl)c2cccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-8-hydroxyquinoline (35.9 g), 2-chloroethyl isocyanate (21.1 g), and triethylamine (2.02 g) were mixed in 400 ml of methyl ethyl ketone and heted at reflux temperature with stirring for about one hour. The reaction mixture, upon cooling to room temperature, yielded the desired 5-chloro-8-quinolinyl N-(2chloroethyl)carbamate as glistening, cream colored cystals, m.p. 146° C.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:19]1([CH2:29][NH2:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([C:29]2[NH:30][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Reactant: NCc1cccc2ccccc12
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccncc1
Yield: 17.5 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (5.0 g) and 1-naphthylmethylamine (3.5 g) were dissolved in toluene (60 ml). The mixture was refluxed under heating for 3 hr while dehydrating with Dean-stark trap. After cooling, the precipitated crystals were collected by filtration and dried to give tert-butyl 2-(1-naphthyl)-5-(4-pyridyl)imidazole-4-carboxylate (1.3 g), melting point 184-190° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[N:23]C(=O)OC)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:16]=[C:15]3[NH2:23])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)N=c1[nH]c2ccccc2n1C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: Nc1nc2ccccc2n1C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 3.64 parts of methyl {2,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-1H-benzimidazol-2-ylidene}carbamate, 24 parts of a hydrochloric acid solution and 40 parts of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is dissolved in water. This solution is alkalized with a concentrated ammonium hydroxide solution. The precipitated product is filtered off, washed with water and dissolved in trichloromethane. The solution is dried, filtered and evaporated, yielding 2.1 parts of 1-[1-(phenylmethyl)-4-piperidinyl]-1H-benzimidazol-2-amine as a residue.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CC(C)([O-])C.[K+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:28]=[N:29][C:30](S(C)=O)=[N:31][CH:32]=2)=[O:26])=[CH:20][CH:19]=1.Cl>C1COCC1.CO.ClCCl.O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]2[CH:32]=[N:31][C:30]([S:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=3)[C:5]([OH:7])=[O:6])=[N:29][CH:28]=2)=[O:26])=[CH:22][CH:23]=1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: O=C(O)c1cccc(S)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1cccc(Sc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c1
Reaction time: 0.05 h
Yield: 23 %

Procedure:
To a solution of 3-mercaptobenzoic acid (83 mg, 0.54 mmol) in THF (2.5 mL) was added potassium tert-butoxide (1 M in THF, 1.1 ML, 1.1 mmol). After 3 min, 2-methane-sulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide was added in one portion and the solution was stirred for 24 h. Water was added, and then the solution was poured into 3% HCl to precipitate the product. The solids were collected by filtration and washed with water. Flash chromatography on SiO2 using a gradient of 5% methanol/dichloromethane to 10% methanol/dichloromethane afforded 15.1 mg (23% yield) of the titled thioether as a white solid. API-MS m/z 370 (MH+), 368 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:19][C:13]2([CH2:16][S:15](=[O:18])(=[O:17])[CH2:14]2)[CH2:12]1)(=[O:10])=[O:9].[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1>>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([N:11]3[CH2:19][C:13]4([CH2:16][S:15](=[O:18])(=[O:17])[CH2:14]4)[CH2:12]3)(=[O:10])=[O:9])=[CH:26][C:21]=2[F:20])=[CH:37][N:38]=1
Reactant: O=S1(=O)CC2(CN(S(=O)(=O)c3ccccc3Br)C2)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N3CC4(C3)CS(=O)(=O)C4)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 6-((2-bromophenyl)sulfonyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H19FN4O4S2, 474.08; m/z found, 474.8 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.56-8.50 (d, J=1.4, 2H), 8.05-7.99 (dd, J=8.0, 1.3, 1H), 7.80-7.73 (m, 1H), 7.69-7.60 (m, 2H), 7.48-7.43 (dd, J=7.6, 1.3, 1H), 7.38-7.32 (dd, J=11.8, 1.8, 1H), 7.31-7.26 (dd, J=7.9, 1.7, 1H), 6.90 (s, 2H), 4.32 (s, 4H), 3.76 (s, 4H).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH3:18])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:19]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:30](I)[C:24]=2[CH:23]=1)(=[O:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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:19]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:30]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=3[O:16][CH2:17][CH3:18])[C:24]=2[CH:23]=1)(=[O:21])[CH3:20]
Reactant: CCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Reactant: CC(=O)c1cc2c(I)cccc2s1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1c(-c2cccc3sc(C(C)=O)cc23)cc(C(C)C)cc1C(C)C

Procedure:
A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-ethoxy phenylboronic acid, 1.62 mmol of 2-acetyl-4-iodo benzo[b]thiophene (see Example 14, step A) and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:5]([Br:7])[N:6]=1.[Li]CCCC.O>C1COCC1>[Br:7][C:5]1[N:6]=[CH:2][S:3][C:4]=1[C:8]1[N:12]2[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[C:11]2=[N:10][C:9]=1[CH3:23]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3Br)c(C)nc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3scnc3Br)c(C)nc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (4.86 g, 10.6 mmol) in THF (150 mL) under N2 atmosphere at −78° C., BuLi (6.63 mL 1.6 M in hexane, 10.6 mmol) is added dropwise for a period of 10 minutes. The mixture is stirred at −78° C. for 30 minutes. Water is added, and the mixture is extracted with Et2O (3×100 mL), dried over MgSO4 and concentrated in vacuo. Crude product is purified by flash chromatography on silica gel (eluent hexane:EtOAc 5:1) to give 3.28 g of the title compound (Yield: 82%). ESIMS: m/z 379, 381 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]([F:79])([F:78])[C:34]1[CH:35]=[C:36]([C:44]([CH3:77])([CH3:76])[C:45]([N:47]([C:49]2[CH:50]=[N:51][C:52]([NH:63][CH:64]([CH2:74][OH:75])[CH2:65][O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])=[CH:53][C:54]=2[C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:56]=2[CH3:62])[CH3:48])=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.[C:80](O)(=[S:82])[CH3:81]>C1COCC1>[F:79][C:33]([F:32])([F:78])[C:34]1[CH:35]=[C:36]([C:44]([CH3:77])([CH3:76])[C:45]([N:47]([CH3:48])[C:49]2[C:54]([C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:56]=3[CH3:62])=[CH:53][C:52]([NH:63][CH:64]([CH2:65][O:66][Si:67]([C:70]([CH3:72])([CH3:73])[CH3:71])([CH3:68])[CH3:69])[CH2:74][O:75][C:80](=[S:82])[CH3:81])=[N:51][CH:50]=2)=[O:46])[CH:37]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:39]=1
Reactant: CC(O)=S
Reactant: Cc1cc(F)ccc1-c1cc(NC(CO)CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OCC(CO[Si](C)(C)C(C)(C)C)Nc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
To a solution of 0.19 mg (0.71 mmol) triphenylphosphine in 10 ml dry THF were added 0.12 g (0.71 mmol) diethyl azodicarboxylate at 0° C. under argon. After 30 min a solution of 0.50 g (0.71 mmol) (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxymethyl-ethylamino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide in 5 ml dry THF and 0.06 g (0.9 mmol) thioacetic acid were added. The reaction mixture was allowed to warm to room temperature over night. Dilution with a saturated aqueous solution of sodium hydrogencarbonate was followed by extraction with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.28 g (52%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([N:28]([CH3:30])[CH3:29])(=[O:32])=[O:31])[CH:25]=[CH:26][C:18]=3[Cl:17])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(=O)(=O)N(C)C)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-dimethylsulfamoyl-benzoic acid (CAS: 37088-27-0; BE 620741) (64%, light yellow foam, MS (m/e): 468.1 (M+H+, 100%)
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]#[N:9].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:8]([C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=1[NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[S:20])#[N:9]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N#CC1=C(N)CCCC1
Product: N#CC1=C(NC(=S)NC(=O)c2ccccc2)CCCC1

Procedure:
Prepared as in Example 1a from 2-aminocyclohex-1-enecarbonitrile (Example 10b) and benzoyl isothiocyanate as a white solid. MS 286 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N+:5]([O-])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:15])C>>[OH:15][CH:7]1[C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc[n+]([O-])c2c1CCCC2
Product: Cc1ccnc2c1CCCC2O
Temperature: 25 °C

Procedure:
A solution of the crude product of Step 1 (19.2 g, 115 mmol) in acetic anhydride (100 ml) was heated at 110° for lh, cooled to room temperature, and evaporated in vacuo. The residue was dissolved in methanol (100 ml) and the solution treated with 4N-NaOH (100 ml). After 2h, the solution was concentrated in vacuo and the aqueous residue partitioned between dichloromethane (100 ml) and water (100 ml). The chlorinated phase was dried (Na2SO4), and evaporated in vacuo to give an oil which was purified by chromatography (silica; ether) to give the product as crystals (12.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[F:10])[C:5]#[N:6].[C:12](=[O:19])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[NH2:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Br:11][C:8]1[C:9]([F:10])=[C:2]([NH:13][C:12](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: N#Cc1cc(Br)c(F)c(Br)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1F
Temperature: 90 °C
Reaction time: 15 h
Yield: 59.9 %

Procedure:
A 500 ml round bottom flask vial was loaded with 3,5-dibromo-4-fluorobenzonitrile (5.7 g, 15.53 mmol) (76% pure, rest di-bromo-regioisomer and tribromo-analog), tert-butyl carbamate (2.63 g, 22.45 mmol) palladium(ii) acetate (177 mg, 0.788 mmol), XANTPHOS (1.14 g, 1.970 mmol) and cesium carbonate (19.3 g, 59.2 mmol). The flask was evacuated and back-filled with nitrogen 2 times. 1,4-Dioxane (200 ml) was added and the flask evacuated and back-filled with nitrogen 2 times. The reaction mixture was heated (with vigorous stirring) to 90° C. for 15 hours in an oil bath. The reaction mixture was cooled to room temperature, filtered through a layer of Celite, evaporated and purified by column chromatography on silica. (750 g cartridge, gradient from 100% hexanes to 20% EtOAc in hexanes, product elutes at −17 to 21 column volumes). tert-butyl (3-bromo-5-cyano-2-fluorophenyl)carbamate (2.93 g) was isolated.