Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][C:7]([F:28])=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][C:7]([F:28])=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1cccc(S(=O)(=O)N2c3ccc(F)cc3-c3cc(F)ccc3C2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccc(F)cc2-c2cc(F)ccc2N1S(=O)(=O)c1cccc(O)c1
Yield: 92 %

Procedure:
The title compound was prepared from 2,9-difluoro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (156 mg, 0.39 mmol), cyclohexene (760 μL, 7.7 mmol), and 1.0 M solution of boron tribromide in dichloromethane (2.33 mL) according to the procedure and in the same manner as described in Example 105, step e. The volatile components were removed in vacuo and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-50% methyl tert-butyl ether in hexane, to afford the desired product (139 mg, 92%) as a white solid, m.p. 165.5-171° C.;
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][N:6]1[C:11]2=[C:12]3[N:16]([C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:10]2[C:9](=[O:30])[N:8]([CH3:31])[C:7]1=[O:32])[CH2:15][CH:14]=[C:13]3[C:24]1[O:25][C:26]([CH3:29])=[CH:27][CH:28]=1.C(=O)=O.C(O)C>C(Cl)Cl.[Pd]>[CH3:5][N:6]1[C:11]2=[C:12]3[N:16]([C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:10]2[C:9](=[O:30])[N:8]([CH3:31])[C:7]1=[O:32])[CH2:15][CH2:14][CH:13]3[C:24]1[O:25][C:26]([CH3:29])=[CH:27][CH:28]=1
Reactant: Cc1ccc(C2=CCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Agent: [Pd]
Agent: O=C=O
Agent: O=C[O-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(C2CCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of ammonium formate (45.6 mg, 0.723 mmol), 1,3-dimethyl-9-(5-methylfuran-2-yl)-5-phenyl-1H-pyrimido[4,5-a]pyrrolizine-2,4(3H,7H)-dione (step 5) (27 mg, 0.072 mmol), and Pd/C (7.69 mg, 7.23 μmol) with a chip of dry ice was added ethanol (1446 μL). The reaction mixture was heated to 60° C. for 25 mins and allowed to stand at RT overnight. The reaction mixture was diluted with DCM and filtered through glass filter paper. The filtrate was washed with water and the organics collected and dried by passing through a phase separator cartridge. The organics were concentrated in vacuo. The crude product was loaded onto a 4 g silica cartridge and purified using an ISCO. The product was eluted with 0-80% EtOAc in iso-hexanes to afford the title compound;
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([NH:10][C:11](=[O:28])[C@H:12]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:13][C:14]([O:16]CC2C=CC=CC=2)=O)[CH2:8][CH2:7][O:6]1)(=[O:3])[CH3:2].[CH2:29](O)[CH3:30]>[Pd]>[C:1]([O:4][C@H:5]1[C@@H:9]([NH:10][C:11](=[O:28])[C@H:12]([CH2:24][CH:25]([CH3:26])[CH3:27])[NH:13][C:14](=[O:16])[NH:10][C:11]2[C:29]3[C:30](=[CH:7][CH:8]=[CH:9][CH:5]=3)[CH:25]=[CH:24][CH:12]=2)[CH2:8][CH2:7][O:6]1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Product: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
(2S, 3S )-2-Acetoxy-3-[[N-benzyloxycarbonyl-(L )leucyl]amino]tetrahydrofuran (3.2 g) was dissolved in ethanol (150 ml) followed by addition of palladium-on-carbon (5%, 1.5 g) and the catalytic hydrogenation was carried out at ambient temperature and atmospheric pressure. The catalyst was then filtered off and α-naphthyl isocyanate (1.5 g) was added to the filtrate. This mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure to obtain (2S,3S)-2-acetoxy-3-[[N-(1-naphthylcarbamoyl)-(L)-leucyl]amino]-tetrahydrofuran (chemical formula below) (2.95 g, 89%). As recrystallized from dichloromethane-methanolisopropyl ether, colorless crystals, m.p. 196°-198° C., optical rotation [α]D -51.8° (c=0.32, CHCl3). ##STR51##
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:4][C:5]1[C:10]([O:11][CH2:2][CH3:3])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Oc1cccnc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccnc1Br
Reaction time: 3.25 h

Procedure:
Iodoethane (26 ml) is added to a mixture of 2-bromo-3-pyridinol (Aldrich, 22.75 g), potassium carbonate anhydrous (32.541 g) and DMF (258 ml). The mixture is stirred at 80°-85° for 3.25 hr, at which time the mixture is cooled in an ice water bath and potassium carbonate is then filtered off and washed with dichloromethane. The filtrate is concentrated under reduced pressure and the residue is dissolved in ethyl acetate (570 ml) and washed with water (300 ml). The aqueous layer is backwashed with ethyl acetate (500 ml) and each of the organic phases are washed with saline (114 ml). The organic phases are combined, dried with magnesium sulfate and concentrated under reduced pressure. The crude material is chromatographed (silica gel; eluting with ethyl acetate/hexane (20/80) to give 2-bromo-3-ethoxypyridine (XXVIIIa, Chart G), MS (m/z) 201, 203; IR (neat) 1448, 1294, 1389, 1420 and 1205 cm-1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:25]=[CH:24][C:11]([S:12][C:13]2[CH:23]=[CH:22][C:16]([C:17](OCC)=[O:18])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.Cl>O1CCCC1>[CH3:7][C:8]1[CH:25]=[CH:24][C:11]([S:12][C:13]2[CH:23]=[CH:22][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(Sc2ccc(C)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(Sc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
To a stirred mixture of lithium aluminum hydride (0.55 g, 14.6 mM) and dry tetrahydrofurane (100 ml) was added a solution (30 ml) of ethyl 4-(4-methylthiophenoxy)benzoate (4.00 g, 14.6 mM) in dry tetrahydrofurane at 0°-10° C., and the mixture was stirred for 12 h at room temperature. To this was added 10% HCl (200 ml) and the mixture was extracted with toluene. The extract was washed with saturated sodium hydrogen carbonate solution and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give 4-(4-methylthiophenoxy)benzyl alcohol (3.13 g, 87%) as colorless crystals, m.p. 103.3° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:11]=2)=[C:6]([F:23])[CH:5]=[CH:4][C:3]=1[OH:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CC(C)=O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:11]=2)=[C:6]([F:23])[CH:5]=[CH:4][C:3]=1[O:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: Oc1ccc(F)c(NCc2cccc(-c3cccc(F)c3)c2)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cccc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.5 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[3-(3-fluorophenyl)phenyl]methylamino]phenol (250 mg, 0.76 mmol, 1.0 eq) in acetone (3 mL) was added Cs2CO3 (297 mg, 0.912 mmol, 1.2 eq). The resulting mixture was stirred for 40 min at room temperature then ethyl bromoacetate (139.4 mg, 0.84 mmol, 1.1 eq) was added. The resulting mixture was stirred overnight then partitioned against water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc 1:0 to 20:1) to give the title compound as an oil (270 mg, 86%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:23])[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH2:21][CH3:22])[C:13]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:5].[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][CH:3]([CH3:23])[C:4]([NH:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH2:21][CH3:22])[C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:5])=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: CCn1c2ccccc2c2cc(CNC(=O)C(C)CN)ccc21
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: CCn1c2ccccc2c2cc(CNC(=O)C(C)CNC(=O)c3ccc(C#N)cc3)ccc21

Procedure:
Using the compound obtained in Step 2 and 4-cyanobenzoic acid, and by the reaction and purification in the same manner as in the method described in Step 3 of Example 36, the title compound was obtained.
Reaction SMILES: N1CCNCC1=O.C(O[C:16]1[CH:29]=[C:28](OCC2C=CC=CC=2)[C:27]([C:38]([N:40]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:49][CH2:50][CH2:51][N:52]4[CH2:57][CH2:56][NH:55][C:54](=[O:58])[CH2:53]4)[CH:46]=3)[CH2:41]2)=[O:39])=[CH:26][C:17]=1[C:18]([N:20]([CH2:22][CH2:23][CH2:24][CH3:25])[CH3:21])=[O:19])C1C=CC=CC=1>>[CH2:22]([N:20]([CH3:21])[C:18](=[O:19])[C:17]1[CH:26]=[C:27]([C:38]([N:40]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:49][CH2:50][CH2:51][N:52]4[CH2:57][CH2:56][NH:55][C:54](=[O:58])[CH2:53]4)[CH:46]=3)[CH2:41]2)=[O:39])[CH:28]=[CH:29][CH:16]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN(C)C(=O)c1cc(C(=O)N2Cc3ccc(OCCN4CCNC(=O)C4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C1CNCCN1
Product: CCCCN(C)C(=O)c1cccc(C(=O)N2Cc3ccc(OCCN4CCNC(=O)C4)cc3C2)c1

Procedure:
Analogous reaction of “A10a” with piperazin-2-one via 2,4-bisbenzyloxy-N-butyl-N-methyl-5-{5-[2-(3-oxopiperazin-1-yl)ethoxy]-1,3-dihydroisoindole-2-carbonyl}benzamide gives the compound N-butyl-N-methyl-5-{5-[2-(3-oxopiperazin-1-yl)ethoxy]-1,3-dihydroisoindole-2-carbonyl}benzamide (“A15”)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][O:22][CH2:23][C:24]([O:26]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:28]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][O:22][CH2:23][C:24](=[O:26])[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)COC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COCC(N)=O
Reaction time: 5 h

Procedure:
A solution of (2S,4R)-1-t-butoxycarbonyl-4-t-butyl dimethylsilyloxy-2-(methoxycarbonylmethyloxymethyl)pyrrolidine (0.75 g) in methanol (21 ml) was saturated with ammonia at ambient temperature and the solution was stirred at the same temperature for 5 hours. The mixture was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (15 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-(carbamoylmethyloxymethyl)pyrrolidine (0.61 g).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>[OH-].[Na+].O1CCOCC1>[NH2:1][C@@H:2]([CH2:3][S:4][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([F:8])=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: Fc1ccc(CBr)cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N[C@@H](CSCc1ccc(F)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
L-cysteine (15.97 g) was dissolved in a mixture of 1.0 M aqueous sodium hydroxide (265 mL) and 1,4-dioxane (265 mL). 4-Fluorobenzylbromide (24.85 g) was added dropwise over 30 min. After stirring overnight, dioxane was removed and the pH of the residual aqueous solution was adjusted to pH-6 with 3M hydrochloric acid. A white precipitate began to form immediately upon addition of the acid and additional water (150 mL) was added to aid stirring of the thick suspension. The reaction mixture was cooled to 0° C. for 1 h and the precipitates were collected by filtration and washed with cold water, Et2O, and hexane, and dried under high vacuum to give 2(R)-amino-3-(4-fluorobenzylsulfanyl)-propionic acid (28.68 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=Cc1ccc(Cl)c(Cl)c1)C2
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(Cc1ccc(Cl)c(Cl)c1)C2
Yield: 84 %

Procedure:
3-(3,4-Dichloro-benzylidene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.0 g, 2.7 mmol) in 10 mL of EtOH and 10 mL of EtOAc was stirred with 25 mg of PtO2 under 1 atm of H2 at rt for 3 h. It was then filtered through a celite bed and the filtrate was concentrated. The residue was purified on a silica gel column to give 0.84 g of 3-(3,4-dichloro-benzyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (M++1: 370).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][C:45]([OH:49])([C:47]#[CH:48])[CH3:46]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:48]#[C:47][C:45]([OH:49])([CH3:46])[CH3:44])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(NC1CCC1)COc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(s1)C(NC1CCC1)COc1ccc(C#CC(C)(C)O)cc1-2
Temperature: 80 °C
Yield: 71.8 %

Procedure:
To a stirred mixture of 9-Bromo-4-cyclobutylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (110 mg, 0.27 mmol) in TEA (5 mL) and DMF (1 mL) were added Pd(OAc)2 (6.0 mg, 0.027 mmol), PPh3 (21.1 mg, 0.081 mmol), CuI (10.2 mg, 0.054 mmol) and 2-methylbut-3-yn-2-ol (113 mg, 1.34 mmol). The reaction mixture was degassed with N2 and heated in autoclave at 80° C. overnight. Then the mixture was cooled to room temperature, and EtOAc was added. The mixture was filtered though Celite, and the filtrate was washed with saturated brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 4-Cyclobutylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (80 mg, 72%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J=2.1 Hz, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 5.51 (s, 1H), 4.44 (m, 1H), 4.3 (m, 1H), 3.95 (m, 1H), 3.22 (m, 1H), 2.14 (m, 2H), 1.7 (m, 2H), 1.52 (m, 2H), 1.48 (s, 6H); LC-MS (ESI & APCI): 413.7 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:35][C:36]([F:58])([F:57])[CH2:37][CH2:38][C:39]1[N:40]=[C:41]([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[N:42]([CH2:44][CH2:45][N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:43]=1.CN1CCCC1=O.C(N(C(C)C)CC)(C)C>O>[CH3:12][C@H:11]1[C:3]2[C:2]([N:54]3[CH2:55][CH2:56][CH:51]([C:41]4[N:42]([CH2:44][CH2:45][N:46]5[CH2:47][CH2:48][CH2:49][CH2:50]5)[CH:43]=[C:39]([CH2:38][CH2:37][C:36]([F:57])([F:35])[F:58])[N:40]=4)[CH2:52][CH2:53]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9](=[O:13])[CH2:10]1
Reactant: FC(F)(F)CCc1cn(CCN2CCCC2)c(C2CCNCC2)n1
Reactant: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(CCC(F)(F)F)cn4CCN4CCCC4)CC3)c21
Temperature: 200 °C

Procedure:
Add (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.33 g, 1.66 mmol), 4-(4-(3,3,3-trifluoropropyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine tris(2,2,2-trifluoroacetate) (1.12 g, 1.0 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (2.30 mL, 8.0 eq) in a microwave tube. Seal with crimp cap. Heat in a microwave reactor at 200° C. for 10 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash with saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with hexanes to 10% methanol/dichloromethane, to give the title compound, (R)-5-methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(3,3,3-trifluoropropyl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one, as an amber solid (0.23 g, 27%). MS (ES) m/z=506 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](COCC[Si](C)(C)C)[N:6]=[C:5]2[NH:19][C:20]1[N:24]([C@H:25]2[CH2:30][CH2:29][C@H:28]([O:31][Si](C(C)(C)C)(C)C)[CH2:27][CH2:26]2)[C:23]2[CH:39]=[CH:40][C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:42][C:22]=2[N:21]=1.O1[CH2:53][CH2:52][O:51][CH2:50]C1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:24]2[C:23]3[CH:39]=[CH:40][C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:42][C:22]=3[N:21]=[C:20]2[NH:19][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:4]4[CH:5]=[N:19][CH:20]=[CH:53][C:52]=4[O:51][CH3:50])[CH:3]=3)[NH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: C1COCCO1
Reactant: CCOC(=O)c1ccc2c(c1)nc(Nc1nn(COCC[Si](C)(C)C)c3ccc(Br)cc13)n2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)nc(Nc1n[nH]c3ccc(-c4cnccc4OC)cc13)n2[C@H]1CC[C@H](O)CC1
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
Ethyl 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1-(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)-1H-benzo[d]imidazole-5-carboxylate (90.1 mg, 0.000121 mol) and 4-methoxypyridin-3-yl-3-boronic acid (22 mg, 0.00014 mol) were added to a 20 mL vial and dissolved in 1,4-dioxane (2 mL, 0.02 mol). To the reaction mixture was added 2 M sodium carbonate in water (0.3 mL) followed by the addition of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexed with dichloromethane (1:1) (10 mg, 0.00001 mol). The reaction mixture was heated under nitrogen at 90° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by combiflash chromatography using methanol/methylene chloride as eluent and a 40 g silica gel cartridge. A gradient was run from 0% methanol to 4% methanol over 20 minutes. Concentrating the product fractions under high vacuum gave 56.8 mg of the title compound as a foam.
Reaction SMILES: BrC(Br)C.Br[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=1.I[C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1>C1COCC1.[Zn]>[F:15][C:9]1[CH:8]=[C:7]([CH2:6][C:17]2[N:18]=[CH:19][N:20]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:21]=2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(Br)Br
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Reaction time: 1 h

Procedure:
Zinc (0.301 g, 4.63 mmol) and dibromoethane (0.040 mL, 0.463 mmol) were stirred in anhydrous THF (2 mL) under Ar for 1.5 h. A solution of 4-bromomethyl-2-fluoro-benzonitrile (as described in Example 1, Step D) (0.546 g, 2.55 mmol) in anhydrous THF (1 mL) was added dropwise and stirred for 1 h. A mixture of 4-iodo-1-trityl-1H-imidazole (0.808 g, 1.85 mmol) and NiCl2 (PPh3)2 (0.120 g, 0.183 mmol) were added together to the reaction. After stirring overnight under Ar, the reaction was quenched with NH4Cl (9 mL), stirred for 2 h, extracted with CH2Cl2 (3×), dried (MgSO4), concentrated and purified using SiO2 chromatography (0.5% MeOH/CH2Cl2 w/NH4OH) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N(C)C2CCCC2)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N(C)C2CCCC2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-cyclopentyl-4,N-dimethyl-benzenesulfonamide (Intermediate 153), the title compound was obtained as a orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([F:20])[CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].C(OC(C1ON=C(C2C=CC(N)=CC=2)C=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:20])[CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])c(F)c2)no1
Agent: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Product: CCOC(=O)c1cc(-c2ccc(N)c(F)c2)no1
Yield: 55 %

Procedure:
The title compound was prepared from 3-(3-fluoro-4-nitro-phenyl)-isoxazole-5-carboxylic acid ethyl ester by following the procedure as described for the preparation of 3-(4-Amino-phenyl)-isoxazol-5-carboxylic acid ethyl ester (Example 1, Step 2) in 55% yield; MS (m/z): 250; 1H NMR (DMSO-d6) δ: 1.31 (t, 3H, CH2CH3), 4.36 (q, 2H, CH2CH3), 5.7 (s, 2H, NH2), 6.81 (t, 1H), 7.48 (d, 1H, J=9.0), 7.56 (d, 1H), 7.74 (s, 1H, 4-H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][N:17]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: COc1ccccc1CBr
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Product: COc1ccccc1CN(Cc1ccco1)S(=O)(=O)c1ccc(C(=O)O)cc1
Yield: 35 %

Procedure:
Prepared as in Example 5-5 from 1-(bromomethyl)-2-methoxybenzene and 4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (Example 5-2b). Yield 35%. MS M+H calculated 402.3. Found 402.0.