Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 60 %

Procedure:
To the solution of 1H-benzoimidazole-5-carboxylic acid (1.62 g, 10 mmol) in THF (20 mL) was added 3,4-dihydro-2H-pyran (2 mL) and camphorsulfonic acid (100 mg, 0.42 mmol, 0.04 equiv). The mixture was refluxed for 24 h under argon. Concentration and chromatography afforded 1.5 g (60%) of 1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carboxylic acid (166) as a light red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cc(Cl)ccc12
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1O

Procedure:
7-Chloro-4-hydroxyquinoline (35 g, 0.195 mol; available from Aldrich, Milwaukee, Wis.) and nitric acid (350 mL of 70%) were combined and heated at reflux for 75 minutes. The reaction mixture was poured over ice while still hot. The resulting bright yellow precipitate was isolated by filtration and then washed 3 times with boiling ethyl acetate to provide 17.3 g of 7-chloro-3-nitro-4-hydroxyquinoline as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[NH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>O>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCC(N)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(CC)CC)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 25.0 g of 4-fluoro-3-nitro-benzoic acid ethyl ester in 100 ml of abs. DMF was added 24.3 g of potassium carbonate, followed by 11.6 g of 3-aminopentane. After 2 h at rt, the mixture was poured into water, and extracted with ethyl acetate three times. The combined organic phases were dried over magnesium sulphate and concentrated to yield 32.8 g (100%) of 4-(1-Ethyl-propylamino)-3-nitro-benzoic acid ethyl ester as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:43]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26]([NH2:43])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)[C@@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@@H](C(N)=O)N2)CCN1C(=O)N(C)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 97 %

Procedure:
In a sealed tube a solution of methyl (2S,5S,7R)-8-{[{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 29, 80 mg, 0.133 mmol) in 7M methanolic ammonia (5 ml, 35.0 mmol) was shaken overnight. The solvent was evaporated and the crude was purified was purified by flash-chromatography (Si cartridge 5 g; from 1:0 to 95:5 DCM/MeOH) to give the title compound (76.1 mg, 0.129 mmol, 98% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.94 (s, 1H) 7.56 (s, 2H) 7.24 (s, 1H) 7.15-7.21 (m, 1H) 6.84-6.96 (m, 2H) 6.71-6.81 (m, 1H) 5.30-5.40 (m, 1H) 4.09-4.18 (m, 1H) 3.47-3.57 (m, 1H) 3.24-3.40 (m, 1H) 2.83 (s, 3H) 2.59-2.78 (m, 2H) 2.31 (s, 3H) 2.03-2.17 (m, 1H) 1.42-1.85 (m, 10H). HPLC: Rt=4.91 mins; MS: m/z=589 [M+H]+ and 611 [M+Na]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[S:6](Cl)(Cl)=[O:7]>O1CCCC1>[S:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:7]
Reactant: O=S(Cl)Cl
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: O=S(c1ncc[nH]1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Imidazole (43.2 g, 635 mmol) was dissolved in tetrahydrofuran (100 ml), and under ice cooling, thionyl chloride (23.5 g, 199 mmol) was added thereto. The reaction mixture was stirred for 3 hours at room temperature, and then the salt thus produced was separated by filtration. Thus, a sulfinyldiimidazole solution was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]([P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:28][CH2:29][C:30](Br)=[O:31]>C(Cl)Cl>[Br:28][CH2:29][C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])=[CH:20][CH:21]=1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: COP(=O)(OC)C(Cc1ccc(N)cc1)P(=O)(OC)OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COP(=O)(OC)C(Cc1ccc(NC(=O)CBr)cc1)P(=O)(OC)OC
Yield: 68.2 %

Procedure:
A solution of 13 (0.959 g, 2.87 mmol) and pyridine (349 μL, 4.31 mmol) in CH2Cl2 was cooled in an ice-bath while stirring. A solution of bromoacetylbromide (250 μL, 2.87 mmol) in CH2Cl2 (5 mL) was added drop-wise and the resulting mixture was stirred for 4 h at that temperature. The reaction was quenched by the addition of water and the product was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude yellow solid was purified by silica gel chromatography resulting in 14 as a colorless solid (0.897 g, 67%). 1H NMR (400 MHz, CDCl3) δ 2.65 (tt, J=6.2, 24.4, 1H), 3.22 (dt, J=6.2, 17.4, 2H), 3.72 (d, J=3.7, 6H), 3.75 (d, J=3.7, 6H), 4.01 (s, 2H), 7.26 (d, J=8.6, 2H), 7.47 (d, J=8.6, 2H), 8.15 (bs, 1H): 31P (162 MHz, CDCl3) δ 26.33 (s, 2P).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]([CH3:10])=O>[OH-].[OH-].[Pd+2]>[CH:8]([NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:10])[CH3:7]
Reactant: NC1CCCC1
Reactant: CC(C)=O
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)NC1CCCC1

Procedure:
Pearlman's catalyst (20% w/w palladium hydroxide-on-carbon) (1.5 g) was added to a solution of cyclopentylamine (15 ml, 0.21 mol) in acetone (200 ml). The reaction mixture was stirred under an atmosphere of hydrogen gas at 414 kPa (60 psi). After stirring for 16 hours the reaction mixture was filtered through Arbocel (trade mark) and the solvent removed under reduced pressure to give the title compound (15 ml) as a thin oil.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26]([OH:28])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.[F:40][C:41]([F:59])([F:58])[O:42][C:43]1[CH:57]=[CH:56][C:46]([CH2:47][CH:48]2[NH:54][CH2:53][CH2:52][CH2:51][NH:50][C:49]2=[O:55])=[CH:45][CH:44]=1>ClCCl>[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26]([N:54]1[CH2:53][CH2:52][CH2:51][NH:50][C:49](=[O:55])[C@H:48]1[CH2:47][C:46]1[CH:45]=[CH:44][C:43]([O:42][C:41]([F:58])([F:59])[F:40])=[CH:57][CH:56]=1)=[O:28])=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: O=C1NCCCNC1Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCCNC(=O)[C@H]1Cc1ccc(OC(F)(F)F)cc1)Cc1cc(F)c(F)cc1F
Temperature: -20 °C
Reaction time: 2 h

Procedure:
N-Methylmorpholine (0.072 mL) and isobutyl chloroformate (0.039 mL) were added to a stirred solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (95 mg) in dichloromethane (5 mL) at −20° C. and the resultant mixture was stirred for 30 min. Hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-one hydrochloride obtained in Step D (91 mg) and IV-methylmorpholine (0.036 mL) were added. The reaction mixture was stirred for 30 min at −20° C. and 2 h at ambient temperature and then evaporated. The residue was purified by preparative TLC (silica gel, methanol/saturated aqueous ammonium hydroxide/dichloromethane 4.4:0.1:95.5), and the isomers were subsequently resolved by HPLC (ChiralPAK OD, 7% ethanol/hexane) to provide the slower eluting (R,R)-isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:17])OCC)=[CH:8][C:7]=1[S:18][CH2:19][CH3:20].[CH3:25][O:26][CH:27]([O:31][CH3:32])[CH2:28][NH:29][CH3:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:29]([CH2:28][CH:27]([O:31][CH3:32])[O:26][CH3:25])[CH3:30])=[O:17])=[CH:8][C:7]=1[S:18][CH2:19][CH3:20]
Reactant: CCOC(=O)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)c(SCC)c1
Reactant: CNCC(OC)OC
Solvent: Cc1ccccc1
Product: CCSc1cc(NC(=O)N(C)CC(OC)OC)ccc1Oc1ccc(Cl)c(Cl)c1

Procedure:
Ethyl [4-(3,4-dichlorophenoxy)-3-(ethylthio)phenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[4-(3,4-dichlorophenoxy)-3-(ethylthio)phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>>[CH3:9][Si:10]([C:13]#[C:14][C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=1)([CH3:12])[CH3:11]
Reactant: Nc1ncc(I)cn1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cnc(N)nc1
Yield: 72.6 %

Procedure:
Prepared from commercially available 2-amino-5-iodopyrimidine (60 g, 271 mmol) and trimethylsilylacetylene (49 mL, 354 mmol) as described in example D.1 method 1 step 1. Obtained the title compound as a light brown solid (37.66 g, 73%). MS (ISP) 192 [(M+H)+].
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]2[NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[C:34]([Cl:46])[CH:33]=1)(C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]2[NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[C:34]([Cl:46])[CH:33]=1
Reactant: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1OCCCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1OCCCN
Reaction time: 1 h
Yield: 94.5 %

Procedure:
TFA (3 mL) was added drop wise to a suspension of (3-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yloxy}-propyl)-carbamic acid tert-butyl ester (0.9 g, 1.59 mmol) in DCM (3 mL). Stir for 1 hour and the reaction mixture was diluted with DCM (20 ml) and sat. NaHCO3 (20 mL). Phases were separated and organic layer was extracted with DCM (20 mL). Organic layers were combined, dried (Na2SO4), and concentrated to give 0.7 g (95%) of desired product.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[CH:11]([S:13]([F:16])(=[O:15])=[O:14])=[CH2:12].O>C(O)(C)C>[F:16][S:13]([CH2:11][CH2:12][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)(=[O:15])=[O:14]
Reactant: C=CS(=O)(=O)F
Reactant: CCNc1cccc(C)c1
Solvent: O
Solvent: CC(C)O
Product: CCN(CCS(=O)(=O)F)c1cccc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Ethyl-m-toluidine (66.5 g) (0.05 m) is dissolved in isopropyl alcohol (75 ml) and vinylsulfonyl fluoride (55 g 0.5) is added dropwise over 1.25 hr. The reaction exotherms to 38° C. and the reaction mixture is stirred for 1 hr. at ambient temperature and drowned into 500 ml of ice and water. The product is collected by filtration, washed with water, and dried in air. The product melts at 32°-34° C.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][NH2:17])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].[CH:20](=O)[CH3:21].[BH4-].[Na+]>CO>[C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][NH:17][CH2:20][CH3:21])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=O
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCN)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNCCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A mixture of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethylamine (1.05 g, 3.50 mmol) and acetaldehyde (1.19 mL, 21.0 mmol) in MeOH (35 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt and NaBH4 (198 mg, 5.25 mmol) was added in portions. The mixture was stirred at rt for 1 h, and the solvents were removed under reduced pressure. The resulting oil was diluted with EtOAc, and the mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1→9:1) yielded the title compound (320 mg, 28%). LC-MS: tR=0.90 min; ES+: 369.22.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH3:9])([OH:3])=[O:2].[N+:10]([O-])([OH:12])=[O:11].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[C:1]([C:4]1[S:5][C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:8]=1[CH3:9])([OH:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccsc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])sc1C(=O)O
Yield: 53 %

Procedure:
To a solution of 2-carboxy-3-methylthiophene (10 g, 70.3 mmol) in 80 mL of trifluoroacetic acid at 0° C. was added HNO3 (1.2 mL,1.0 eq.) dropwise. The reaction mixture was warmed to ambient temperature and after 4 hours another 1.0 eq. of HNO3 was added. The reaction mixture was made basic with aqueous sodium bicarbonate and washed with ethyl acetate. The aqueous layer was acidified with concentrated HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 5.75 g (53%) of 2-carboxy-3-methyl-5-nitrothiophene and 2-carboxy-3-methyl-4-nitrothiophene, as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:23][CH:24]=O.[CH:26]1([NH:32][C:33]2[C:38]3[N:39]=C(S(C)(=O)=O)[N:41]=[CH:42][C:37]=3[CH:36]=[CH:35][N:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:32][C:33]2[C:38]3[N:39]=[C:24]([NH:23][C:4]4[CH:5]=[CH:6][C:7]([C:9]5[CH:10]=[N:11][N:12]([CH2:14][CH2:15][N:16]6[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]6)[CH:13]=5)=[CH:8][C:3]=4[O:2][CH3:1])[N:41]=[CH:42][C:37]=3[CH:36]=[CH:35][N:34]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1cc(-c2cnn(CCN3CCN(C)CC3)c2)ccc1NC=O
Reactant: CS(=O)(=O)c1ncc2ccnc(NC3CCCCC3)c2n1
Product: COc1cc(-c2cnn(CCN3CCN(C)CC3)c2)ccc1Nc1ncc2ccnc(NC3CCCCC3)c2n1
Yield: 48 %

Procedure:
The title compound was prepared according to Example 40 above using N-(2-methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)formamide (Preparation 61) and N-cyclohexyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 44). The residue was purified by silica gel column chromatography eluting with 0 to 15% MeOH in DCM to give the title compound (51 mg, 48%).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cccc(I)c1
Product: C[Si](C)(C)c1cccc(Br)c1

Procedure:
1-Bromo-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1-bromo-3-iodobenzene as the dihalo compound of formula (II).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1B(O)O)[CH:13]([CH3:15])[CH3:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[O:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Cc1ccc(B(O)O)c(OCC(C)C)c1
Reactant: Clc1nc2c(Br)cccn2n1
Product: Cc1ccc(-c2cccn3nc(Cl)nc23)c(OCC(C)C)c1

Procedure:
2-Chloro-8-(2-isobutoxy-4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-isobutoxy-4-methylphenylboronic acid in a manner analogous to Example 2c (0.48 g, 71%). MS=316 (MH)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[CH:36]1([CH2:35][C:17]([CH3:22])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([O:20][CH3:21])=[O:19])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COC(=O)C(C)c1ccccc1
Reactant: BrCC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)(CC1CCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 184.2 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 3.04 mL, 3.04 mmol, 1 equiv) under a N2 atmosphere was cooled to 0° C. and treated with a solution of methyl 2-phenylpropionate (0.500 g, 3.04 mmol, 1 equiv) in dry tetrahydrofuran (2 mL). The reaction was stirred at 0° C. for 2 hrs, then cooled to −78° C. and treated with hexamethylphosphoric triamide (0.4 mL) and bromomethylcyclopentane (0.745 g, 4.568 mmol, 1.5 equiv). Stirred the reaction at −78° C. and allowed the bath to slowly warm to room temperature overnight. After 15 hrs, the reaction mixture was quenched with 10% aq NH4Cl (50 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with H2O (50 mL) and brine, then dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was purified by SiO2 flash chromatography with 2:3 dichloromethane/hexanes to give the product as colorless oil (1.38 g, 5.60 mmol, 92%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.90-1.12 m, 2 H) 1.32-1.72 m, 10 H) 1.97-2.12 (m, 2H) 3.58 (s, 3 H) 7.19-7.35 m, 5 H); MS (APCI+) m/z 247 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:35](O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[CH3:35])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a suspension of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1000 mg) and paraformaldehyde (138 mg) in dichloromethane (20 ml) were added acetic acid (0.26 ml) and sodium cyanoborohydride (144 mg) in an ice bath. The mixture was stirred at room temperature overnight and then methanol (20 ml) was added. The resulting mixture was stirred at 30° C. for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/2 as an eluant to give the desired compound (761 mg, yield 74%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14]#[N:15])[N:11]=[CH:10]1.C[NH:19]O.Cl.CCN(CC)CC>CCO>[F:17][C:2]([F:16])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14](=[NH:19])[NH2:15])[N:11]=[CH:10]1
Reactant: N#Cc1cn(-c2ccccc2C(F)(F)F)cn1
Reactant: CNO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(N)c1cn(-c2ccccc2C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carbonitrile (374 mg, 0.8 mmol), MeNHOH.HCl (167 mg, 2 mmol), Et3N (0.5 mL), and dry EtOH in a sealed vial was stirred at 80° C. for 2 h, the volatiles were removed in vacuo to give N-hydroxy-N-methyl-1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carboximidamide as a white solid, which was used in next reaction without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[CH:24]=3)=[CH:16][C:14]=2[N:15]=1.[CH2:29]([NH2:32])[CH2:30][CH3:31]>>[CH2:29]([NH:32][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[CH:24]=3)=[CH:16][C:14]=2[N:15]=1)[CH2:30][CH3:31]
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4cc5ccccc5o4)ccc3o2)c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-(2-benzofuranyl)benzoxazole (200 mg, 0.53 mmol), and propylamine (3 ml) the subtitle compound was obtained (199 mg, 91%). The product was used directly in the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.CCN(C(C)C)C(C)C.[C:17]([O:21][C:22]([NH:24][C:25]1([CH:31]([OH:35])[C:32](O)=[O:33])[CH2:28][C:27]([F:30])([F:29])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:17]([O:21][C:22](=[O:23])[NH:24][C:25]1([CH:31]([OH:35])[C:32](=[O:33])[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[CH2:28][C:27]([F:29])([F:30])[CH2:26]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)O)CC(F)(F)C1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)C(O)C2(NC(=O)OC(C)(C)C)CC(F)(F)C2)n1
Reaction time: 2 h
Yield: 92 %

Procedure:
1-Methyl-1H-pyrazol-3-amine (158 mg, 1.63 mmol) and DIEA (1.08 mL, 6.52 mmol) was added to a solution of (1-tert-Butoxycarbonylamino-3,3-difluoro-cyclobutyl)-hydroxy-acetic acid (1.63 mmol) dissolved in DMF (20 mL). The solution was cooled to 0° C. and after 10 minutes HATU (620 mg, 1.63 mmol) was added. After approximately 2 hours at RT, LC-MS showed product and no starting material and the solvent was removed by rotary evaporation. The crude product was dissolved in 40 mL EtOAc and washed with 25 mL sat. NaHCO3 (aq). The organic phase was dried with Na2SO4, filtered and evaporated to dryness. The crude product was purified on a 25 g silica column on a Biotage Flashmaster, which gave the title product as a white solid (92%). TLC rf: 0.07 in heptane:ethyl acetate 1:1.