Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[CH2:42](O)[CH2:43][CH2:44]C>>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:36])([CH3:37])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32]([O:34][CH2:35][CH2:42][CH2:43][CH3:44])=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Reactant: CCCCO
Agent: C[O-]
Agent: [Na+]
Product: CCCCOC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1

Procedure:
Prepared analogously to Example 7 by reacting methyl 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylate with sodium methoxide in n-butanol.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Br:9]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[Br:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CNc1ccncc1
Solvent: C1CCOC1
Product: CNc1ccncc1Br
Yield: 112.4 %

Procedure:
To a solution of 10.6 g (98 mmol) 4-(N-methylamino)-pyridine in 200 ml tetrahydrofuran was added dropwise a solution of 14.0 g (49 mmol) 1,3-dibromo-5,5-dimethylhydantoin in 50 ml tetrahydrofuran at room temperature within 1.5 h. The solvent was removed and the residue was re-dissolved in ethyl acetate. The organic phase was washed four times with saturated sodium carbonate solution, dried (sodium sulfate) and evaporated. The residue was purified by flash chromatography to give 10.3 g (56%) of the title compound as white crystals.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:44]=[C:43]([C:45]([OH:47])=O)[CH:42]=[CH:41][C:40]=2[C:48]2[C:53]([O:54][CH3:55])=[CH:52][CH:51]=[CH:50][C:49]=2[O:56][CH3:57])=[CH:35][C:34]=1[O:58][CH2:59][CH2:60][CH2:61][N:62]([CH3:64])[CH3:63].[NH2:65][C:66]1([C:72]([OH:74])=[O:73])[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Cl>CN(C=O)C.C(#N)C.CCOC(C)=O.CCOCC.O>[ClH:32].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:44]=[C:43]([C:45]([NH:65][C:66]3([C:72]([OH:74])=[O:73])[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]3)=[O:47])[CH:42]=[CH:41][C:40]=2[C:48]2[C:49]([O:56][CH3:57])=[CH:50][CH:51]=[CH:52][C:53]=2[O:54][CH3:55])=[CH:35][C:34]=1[O:58][CH2:59][CH2:60][CH2:61][N:62]([CH3:64])[CH3:63]
Reactant: COc1cccc(OC)c1-c1ccc(C(=O)O)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Reactant: NC1(C(=O)O)CCCCC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cccc(OC)c1-c1ccc(C(=O)NC2(C(=O)O)CCCCC2)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Add, under argon, 0.74 mL (0.41 mmol) of diisopropylethylamine and 409 mg (1.28 mmol) of TBTU to a solution of 200 mg (0.42 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylic acid in 50 mL of anhydrous DMF. In parallel, heat, while stirring under argon, a mixture of 84 mg (0.59 mmol) of 2-aminocyclohexane-2-carboxylic acid and 0.18 mL (0.76 mmol) of N,O-bis(trimethylsilyl)acetamide (BSA) in 5 mL of anhydrous acetonitrile to 90° C. After 2 h, the mixture has dissolved completely. Cool the solution to RT, then add it to the solution of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2 carboxylic acid activated with TBTU. After stirring for 18 h at RT, add 10 mL of 0.5N HCl aqueous solution and continue stirring for 3 h. Then distribute the reaction mixture in a mixture of 20 mL of EtOAc/ether 1:1 and 10 mL of water. After extraction, extract the aqueous phase again with 10 mL of 1:1 ether/EtOAc mixture. Combine the organic phases, wash with 2×10 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Then purify the residue by reverse-phase HPLC (RP18) eluting with a 0.01N HCl/acetonitrile gradient from 5% to 100% of acetonitrile. After concentration under reduced pressure and tyophilization, we obtain 106 mg of 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride in the form of white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-])=O)[CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[NH2:13]
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
A mixture of 1-methoxy-3-nitro-5-(trifluoromethyl)benzene (8.50 g, 38.4 mmol) and 10% Pd/C (2.00 g, 1.88 mmol) in methanol (40 mL) was stirred under hydrogen balloon at rt for 24 h, and filtered through a pad of celite and concentrated to give the title product (7.2 g) as an orange solid
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>C1(C)C=CC=CC=1.N1CCCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:12](\[C:10]#[N:11])/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C(C#N)=C/c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a solution of 4-bromobenzaldehyde (106 g, 573 mmol) in toluene (1000 mL) were added ethyl 2-cyanoacetate (71.3 g, 630 mmol) and piperidine (976 mg, 11.5 mmol) and the clear, light brown solution was heated at reflux for 5 h in a 4-neck flask equipped with a Dean-Stark trap, then stirred overnight at room temperature. After cooling the reaction mixture was evaporated, the residue suspended in heptane (500 mL), homogenized in an ultrasound bath for min, stirred for 20 min at 50° C., then the precipitate was collected by filtration. This was dissolved in ethyl acetate (1000 mL) and heptane (500 mL), then slowly concentrated at 50° C. to a volume of approximately 300 mL of solvent. This solution started to crystallize upon standing. The precipitate (96 g) was collected by filtration and washed with heptane/ethyl acetate 9:1 (300 mL). The mother liquor was concentrated at 50° C. until crystallization started. The product was allowed to precipitate over 1 h at room temperature, then collected by filtration to produce a second crop of product (44 g). Total yield: 140 g (87%). Light yellow solid, MS: 299.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@:7]2([OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])=[CH:5][CH:4]=[N:3]1.CN(C1C=CC=CN=1)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]([C@:7]23[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:24](=[O:25])[O:14]3)=[CH:5][CH:4]=[N:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1nccc1[C@]1(O)CCCC[C@H]1O
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: Cn1nccc1[C@]12CCCC[C@H]1OC(=O)O2
Yield: 91.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 167a by using the (1R,2R)-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol (1.21 g, 6.17 mmol) prepared in Example 168a, dimethylaminopyridine (75.3 mg, 0.62 mmol), carbonyldiimidazole (3.50 g, 21.6 mmol) and toluene (20 mL), to yield the title compound (1.26 g, 92%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:13]([NH2:14])=[C:12]([Cl:15])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[OH:16])([O-])=O>C(O)C.[Pt]>[NH2:1][C:4]1[C:13]([NH2:14])=[C:12]([Cl:15])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[OH:16]
Reactant: COC(=O)c1cc(Cl)c(N)c([N+](=O)[O-])c1O
Agent: [Pt]
Solvent: CCO
Product: COC(=O)c1cc(Cl)c(N)c(N)c1O

Procedure:
Methyl 3-nitro-4-amino-5-chlorosalicylate (4.1 g, 0.017 mmol) is hydrogenated at 45 initial psi in 450 ml ethanol for 30 minutes using 2.1 g of 10% Pt/C. The catalyst is then filtered (celite) and washed with ethylacetate (450 ml) and the filtrate evaporated in vacuo to give methyl 3,4-diamino-5-chlorosalicylate which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c21
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCc1cncc(-c2cc(F)c3c(c2)CCC(=O)N3C)c1
Temperature: 120 °C
Yield: 49.8 %

Procedure:
A mixture of 8-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (20 mg, 0.066 mmol), ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 27.4 mg, 0.098 mmol), bis(triphenylphosphine)-palladium(II) chloride (4.6 mg, 0.0066 mmol) and aq. sodium carbonate solution (2 N, 0.07 mL) in DMF (1 mL) was heated in a microwave at 120° C. for 30 min. The resulting reaction mixture was then diluted with EtOAc, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (12.4 mg, 50%) as a white solid. MS: 378.1 (M+H+)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C@@H:6]2[CH2:5][CH2:4]1.Cl[C:14]1[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][C@@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: Fc1cnc(Cl)nc1
Reactant: OC[C@H]1CC[C@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A mixture of 2.31 g (13.6 mmol) of (7S,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 2), 1.98 g (15.0 mmol) of 2-chloro-5-fluoropyrimidine (B. Baasner, E. Klauke, J. Fluorine Chem., 1989, 45, 417), 4.32 g (40.8 mmol) of sodium carbonate and 50 mL of water was heated at reflux for 16 h. The mixture was cooled to room temperature and extracted with chloroform (3×). The combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 chloroform:methanol gave, 2.7 g (75%) of the title compound. mp (base) 111–112° C. 13C NMR (base, CDCl3): δ 26.5, 27.3, 34.2, 44.3, 49.8, 54.8, 58.8, 60.7, 68.2, 145.0, 145.3, 149.9, 153.2, 158.6. HRMS calcd for C13H19FN4O: 266.1543, found: 266.1530.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18]>CC(C)=O>[CH2:17]([O:19][C:20]([CH2:21][O:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])=[O:23])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: O=C(CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a solution of 10 g of 2-hydroxyacetophenone in 40 ml of acetone, 12 g of potassium carbonate was added, and after the mixture was agitated for 1 hour at room temperature, 14 g of bromoacetic acid ethyl ester was added dropwise while stirring, and the resultant mixture was agitated for 3 hours. The reaction mixture was filtered and acetone was evaporated, leaving a residue which was extracted with ether. Evaporation of ether left a residue, which was recrystallized from petroleum ether to give 9.7 g of 2-(ethoxycarbonylmethoxy)-acetophenone, m.p. 33°-35° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[NH:21][N:20]=2)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])(=[O:9])=[O:8])=[CH:4][CH:3]=1.Cl[CH2:31][C:32]1[CH:44]=[CH:43][C:35]([C:36]([N:38]([CH2:41]C)[CH2:39]C)=[O:37])=[CH:34][CH:33]=1.[OH-].[K+]>>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[N:21]([CH2:31][C:32]3[CH:44]=[CH:43][C:35]([C:36]([N:38]([CH3:39])[CH3:41])=[O:37])=[CH:34][CH:33]=3)[N:20]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cccc2[nH]nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c12
Reactant: CCN(CC)C(=O)c1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Product: COc1cccc2c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(C(=O)N(C)C)cc1
Temperature: 50 °C
Yield: 61.5 %

Procedure:
A solution of 5-chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (Intermediate 8) (150 mg, 0.32 mmol) was treated with 4-(chloromethyl)-N,N-diethylbenzamide (86 mg, 0.38 mmol) and potassium hydroxide (21.3 mg, 0.38 mmol), and the mixture was heated to 50° C. overnight. Reaction mixture was partitioned between DCM (3 mL) and water (3 mL). The organic phase was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried (hydrophobic frit) and concentrated under a nitrogen stream in a blowdown unit. The residue was purified by chromatography using a Flash Master system (Solo machine), on a 50 g silica cartridge, eluting with 0 to 100% A in B, A being a 20% EtOAC in DCM solution and B being neat DCM over 60 min. Evaporation of the appropriate fractions gave the title compound (125 mg, 60%) LCMS (System A) RT=1.52 min, ES+ve m/z 680/682 (M+NH4)+.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.C(#N)C.[Cl:9][C:10]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:19][C:18]1[C:10]([Cl:9])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([C:4]#[N:5])=[O:13]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: N#C[Cu]C#N
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#CC(=O)c1cccc(Cl)c1Cl

Procedure:
In a mixture of 128 gm. of copper cyanide, 120 ml. of acetonitrile and 200 ml. of toluene, the solution of 200 gm. of 2,3-dichlorobenzoylchloride (II) in 250 ml of toluene was added. The reaction mixture was refluxed for 16 hour. After filtration, the solvent was removed under reduced pressure to give 200 ml of oily 2,3-dichlorobenzoyl cyanide (III).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]([C:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:16]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(C)(C)C>CO>[ClH:1].[CH:26]1([CH:16]([N:15]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:32]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:17]([NH:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N(C(=O)c1ccccc1)C(C(=O)NC1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: CO
Product: O=C(NC1CCCCC1)C(C1CCCCC1)n1c(-c2ccccc2)nc2ccccc21
Temperature: 145 °C

Procedure:
Concentrated HCl (25% in water, 0.5 mL) was added to a solution of {2-[benzoyl-(cyclohexyl-cyclohexylcarbamoyl-methyl)-amino]phenyl}-carbamic acid tert-butyl ester (64 mg, 0.12 mmol) in methanol (2.0 mL). The reaction mixture was heated in a focussed microwave (CEM Discovery) at 145° C., for 3 minutes with stirring. The reaction mixture was then evaporated to afford 2,N-dicyclohexyl-2-(2-phenyl-benzoimidazol-1-yl)-acetamide hydrogen chloride, 46 mg (85%) as a pale yellow solid. MS (ES+): 416 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12](=[O:15])([O-])[O-:13].[Cs+].[Cs+].O>CN(C=O)C>[CH3:8][C:7]1[C:2]([NH:1][C:12](=[O:15])[O:13][C:7]([CH3:8])([CH3:2])[CH3:6])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cnc1NC(=O)OC(C)(C)C

Procedure:
2-Amino-3-methyl-5-nitropyridine (1 g, 6.5 mmol) and di-tert-butyl Bicarbonate (2.2 g, 9.8 mmol) were added in DMF (33 mL), then cesium carbonate (6.4 g, 19.6 mmol) at room temperature for 6 hours. Water (200 mL) was added, extracted with ethyl acetate (200 mL), second wash with brine (100 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 13% ethyl acetate/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:23]1[CH:24]=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:29]>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>[F:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][O:38][C:26]2[CH:25]=[CH:24][C:23]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:37][C:27]=2[C:28]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:29])=[CH:41][CH:42]=1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)Nc3cccnc3)c2)cn1
Temperature: 120 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.37 mmol), 1M sodium carbonate (0.75 ml, 0.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (25.9 mg, 0.02 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared as described in Example 59; 150 mg, 0.37 mmol) in 1,2-dimethoxyethane (4 ml). The reaction was heated at 120° C. for one hour. The solvent was removed in vacuo to give a residue. Purification by MDAP yielded the title compound as a white solid. 70 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[N:38]#[C:39]Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:39]#[N:38])[CH2:13][CH2:12]1)[C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])=[O:4]
Reactant: N#CBr
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C#N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of 3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (197 mg, 0.45 mmol) in CH2Cl2 (4.5 mL) was treated with K2CO3 (93 mg, 0.67 mmol) and cyanogen bromide (100 mg, 0.94 mmol). The reaction mixture was stirred at room temperature for 1 hour and heated at reflux for 18 h. The mixture was cooled at room temperature and filtered on celite. The filtrate was washed with AcOH (1N) and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using (2% MeOH/CH2Cl2) to provide 3-[(1-cyano-piperidin-4-yl)-(4-methyl cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (154 mg, 74% yield) as pale yellow foam.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH3:22])[C:10]=1[F:23].[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH3:22])[C:10]=1[F:23])[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC1CCCCCN1c1ncnc(Cl)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(N2CCCCCC2C)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 118.6 %

Procedure:
0.07 g of sodium hydride (60% oil suspension) was suspended in 2 ml of tetrahydrofuran. 0.5 ml of tetrahydrofuran solution of 0.10 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.5 ml of tetrahydrofuran solution of 0.20 g of 1-(6-chloro-5-fluoropyrimidin-4-yl)-2-methyl-hexahydro-1H-azepine at room temperature, and stirred for 6 hours at 60° C. After the reaction mixture was cooled to near room temperature, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, 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 0.27 g of 1-(6-(2-butynyloxy)-5-fluoropyrimidin-4-yl)-2-methyl-hexahydro-1H-azepine (hereinafter, referred to as Compound (47)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:6].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C)C=O.C(OCC)(=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:5]([C:4]1[CH:3]=[C:2]([CH:17]=[CH:16][CH:15]=1)[O:1][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:6]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NCc1ccccn1)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)NCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
23.8 g (0.10 mol) of 3-hydroxy-N-(pyridin-2-ylmethyl)-benzamide (stage B of Example 42) are added portionwise to the suspension of 4.5 g (0.10 mol) of sodium hydride (55% dispersion in oil) in 400 ml of N,N-di-methylformamide at 0° C. under argon, followed, after 10 minutes, by 15.4 ml (0.10 mol) of tert-butyl 2-bromo-acetate. The mixture is stirred at ambient temperature for 1 hour. The reaction medium is diluted with ethyl acetate and extracted with water. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The white solid is taken up in diisopropyl ether, filtered and dried, to give 26.3 g (74%) of a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C-]#N.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]([CH:4]([C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])[OH:5])=[O:5]
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(Cl)cc1Cl)C(O)c1ccc(Cl)cc1Cl
Temperature: 105 °C

Procedure:
To a mixture of 2,4-dichlorobenzaldehyde (5.0 gm, 29 mmol) in ethanol (10 mL) was added a solution of sodium cyanide (500 mg, 10 mmol) in water (5 mL). The reaction was heated to reflux (100-110° C.) for 1 hr and was then cooled, diluted with water, and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (10% methylene chloride, 10% ethyl acetate in hexanes) to afford the title compound as an oil.