Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16].CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:9]2[CH:8]3[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH:10]2[CH2:11][C:12](=[O:14])[CH2:13]3)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: O=C1C=CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C(c2ccccc2I)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: O=C1CC2c3ccccc3C(C1)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 12.1 %

Procedure:
To a solution of compound 15 (1.65 g, 3.25 mmol) in benzene (300 mL) at 80° C. was added a solution of AIBN (105 mg, 20% mol) and tri(n-butyl)tin hydride (0.86 mL, 3.25 mmol) in benzene (20 mL) over a 2 hour period. The mixture was heated at reflux for 48 h. After evaporation of the solvent, the residue was purified via flash chromatography on silica gel to give a white solid as the product (16) (150 mg, 12%). 1H NMR (CDCl3) δ 7.66 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.0-6.9 (m, 4H), 5.25 (dd, J=3.3 Hz, 2H), 3.14 (dd, J=4.5, 16.8 Hz, 2H), 2.58 (d, J=16 Hz, 2H).
Reaction SMILES: CC1C=[C:5]([CH3:7])[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.N1CC[O:29][CH2:28][CH2:27]1>>[NH2:20][C:8]([N:4]1[CH2:5][CH2:7][O:29][CH2:28][CH2:27]1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=C(N)N2CCOCC2)cc1

Procedure:
The compound of Example 3 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of morpholine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 283.35; found mol. wt. (M+H) 284.1
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[C:19]1([C:25]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[S:28](=[O:35])(=[O:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:36]1([C:25]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:33]3[CH:29]([CH2:30][N:31]([C:15](=[O:16])[CH2:14][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:32]3)[S:28](=[O:34])(=[O:35])[CH2:27][CH2:26]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=S1(=O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CC2C(C1)S(=O)(=O)CCC2(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.35 cm3 of triethylamine and a solution of 0.17 cm3 of phenylacetyl chloride in 5 cm3 of dichloromethane are added to a suspension, cooled to 0° C., of 0.46 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide hydrochloride in 10 cm3 of dichloromethane. After stirring for 1 hour at 0° C. and then 1 hour at 20° C., the reaction mixture is diluted with 10 cm3 of dichloromethane, washed twice with 30 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 30 cm3 of ethyl ether, the crystals are drained and dried. 0.50 g of (4aRS,7aRS)-4,4-diphenyl-6-phenylacetylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of white crystals.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:33])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[C:8]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)([CH3:3])[CH3:2].[CH2:34](Br)[CH3:35].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:34]([N:21]1[CH2:22][CH2:23][CH2:24][N:18]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[N:7]([CH2:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:33])[C:16]3=[O:17])[CH2:19][CH2:20]1)[CH3:35]
Reactant: COc1cccc(-c2nc3ccc(N4CCCNCC4)cc3c(=O)n2CC(=O)NC(C)C)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCCN(c2ccc3nc(-c4cccc(OC)c4)n(CC(=O)NC(C)C)c(=O)c3c2)CC1
Yield: 10 %

Procedure:
A mixture of N-isopropyl-2-[2-(3-methoxyphenyl)-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl]acetamide (EXAMPLE 2a) hydrochloride salt (50 mg, 0.103 mmol), ethyl bromide (22 mg, 0.21 mmol), and K2CO3 (43 mg, 0.31 mmol) in acetonitrile (5 mL) was heated to reflux for 24 h. The mixture was then cooled, filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 2-[6-(4-ethylperhydro-1,4-diazepin-1-yl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 4a) (5.1 mg, 0.010 mmol, 10%) as the hydrochloride salt.
Reaction SMILES: [O:1]1[C:5]([CH2:6][C:7]([OH:9])=O)=[CH:4][N:3]=[CH:2]1.[CH:10]1([O:14][C:15]2[CH:16]=[C:17]([N:23]3[CH2:28][CH2:27][NH:26][C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24]3)[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:14][C:15]2[CH:16]=[C:17]([N:23]3[CH2:28][CH2:27][N:26]([C:7](=[O:9])[CH2:6][C:5]4[O:1][CH:2]=[N:3][CH:4]=4)[C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24]3)[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)Cc1cnco1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3cnco3)[C@@H](CC(C)C)C2)cc1OC1CCC1
Yield: 4 %

Procedure:
Prepared by the method outlined for Example 189 using 2-(oxazol-5-yl)acetic acid and (S)-1-(3-cyclobutlyoxy-4-methoxy-phenyl)-3-isobutyl-piperazine as starting material. Product was obtained as an oil (4%). LC/MS (Method B) 3.62 min, [M+1]+ 428.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43]C)[C:35]([N:37](C)[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>CC(CC)=O.C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH3:43])[C:35]([NH:37][CH:38]3[CH2:4][CH2:3][CH2:2][CH2:1][CH2:5]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)N(C)C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: CCC(C)=O
Solvent: Cc1ccccc1C
Product: CCCCc1nc2ccc(N(CCCC)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-6-(N-(dimethylaminocarbonyl)-n-pentylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylethylketone/xylene=1:1)
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:27]2[CH2:29][CH2:28]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[CH2:33][CH3:34]>>[CH:27]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:30][N:31]=[C:32]([CH2:33][CH3:34])[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]#[N:26])=[CH:22][CH:23]=3)=[N:14][CH:13]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: N#CCc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1
Reactant: CCC(=N)NO
Product: CCc1noc(N2CCC(N(C(=O)c3cnc(-c4ccc(CC#N)cc4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 2-(4-cyanomethyl-phenyl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-propionamidine following a procedure analogous to that described in Example 6. LC (method 3): tR=1.86 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:49]=[CH:48][C:24]([C:25]([NH:27][S:28]([C:31]4[CH:36]=[CH:35][C:34]([NH:37][CH2:38][CH:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[C:33]([N+:45]([O-:47])=[O:46])[CH:32]=4)(=[O:30])=[O:29])=[O:26])=[C:23]([O:50][C:51]4[CH:52]=[C:53]5[C:57](=[CH:58][CH:59]=4)[NH:56][CH:55]=[CH:54]5)[CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:49]=[CH:48][C:24]([C:25]([NH:27][S:28]([C:31]4[CH:36]=[CH:35][C:34]([NH:37][CH2:38][CH:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[C:33]([N+:45]([O-:47])=[O:46])[CH:32]=4)(=[O:30])=[O:29])=[O:26])=[C:23]([O:50][C:51]4[CH:52]=[C:53]5[C:57](=[CH:58][CH:59]=4)[NH:56][CH2:55][CH2:54]5)[CH:22]=3)[CH2:19][CH2:20]2)=[CH:6][CH:7]=1
Reactant: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1Oc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1Oc1ccc2c(c1)CCN2

Procedure:
A suspension of EXAMPLE 40D (22.57 mg) and sodium cyanoborohydride (25 mg) in acetic acid (5 ml) was stirred at room temperature for 2 hours. The product was partitioned between dichloromethane and water. The organic layer was separated, dried over Na2SO4, and concentrated. The crude product was purified by RP HPLC (C8, 30-100 acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.56 (s, 1H), 9.60 (s, 1H), 8.66 (t, 1H), 8.57 (d, 1H), 7.85 (dd, 1H), 7.71 (s, 1H), 7.46-7.60 (m, 5H), 7.29-7.42 (m, 3H), 7.25 (d, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 6.73 (d, 1H), 6.36 (s, 1H), 4.32 (bs, 2H), 3.85 (dd, 4H), 3.59 (t, 4H), 3.35 (t, 2H), 3.27 (t, 2H), 3.02 (t, 4H), 1.80-1.99 (m, 1H), 1.62 (d, 2H), 1.15-1.36 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[O:19]CC2C=CC=CC=2)[O:7][C:8]=1[O:9][CH2:10][CH3:11])[CH3:3]>C(OCC)(=O)C.[Pd]>[CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:12]2[C:13]([OH:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[O:7][C:8]=1[O:9][CH2:10][CH3:11])[CH3:3]
Reactant: CCOc1oc(-c2c(Cl)cccc2OCc2ccccc2)nc1C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1oc(-c2c(O)cccc2Cl)nc1C(C)C
Temperature: 25 °C
Reaction time: 0.38 h

Procedure:
0.4 g 4-(2-propyl)-5-ethoxy-2-(2-benzyloxy-6-chlorophenyl)oxazole was dissolved in 10 ml ethyl acetate. To the solution, 5% palladium/carbon in an amount of 0.11 g was further added, and the solution was stirred under hydrogen atmosphere for 15-30 min. at room temperature. The solution reacted was filtrated, then the filtrate was condensed under reduced pressure, affording the objective substance in an amount of 0.28 g.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:19])=[C:14]([O:17]C)[CH:15]=2)[C:10]([CH3:21])([CH3:20])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:19])=[C:14]([OH:17])[CH:15]=2)[C:10]([CH3:20])([CH3:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1C)C(C)(C)C(=O)N2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(cc1O)N(Cc1ccccc1)C(=O)C2(C)C
Temperature: -20 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 1-benzyl-6-methoxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (1.52 g, 5.15 mmol) in anhydrous dichloromethane (50 mL) was added slowly, under argon at −78° C., BBr3 (0.87 mL, 9.27 mmol). The reaction was warmed up to −20° C. and stirred overnight at room temperature. Water and the layer separated. The aqueous layer was neutralized with NaHCO3 and extracted with dichloromethane. The organic combined extract was washed with aqueous NaHCO3, water and brine, dried over MgSO4, filtered and evaporated to give 1-benzyl-6-hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (93% yield). 1H NMR (300 MHz; CDCl3): 1.38 (s, 6 H), 2.19 (s, 3 H), 4.82 (s, 2 H), 5.47 (br s, 1 H), 6.26 (s, 1 H), 6.93 (s, 1 H), 7.26 (m, 5 H).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH2:10](Br)[C:11]#[CH:12].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]=[O:18]>C1COCC1.[Zn]>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]([OH:18])[CH2:12][C:11]#[CH:10]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: C#CCBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C#CCC(O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
General Procedure BB: To a mixture of zinc (0.60 g, 9.2 mmol) in THF (1 mL) was added 1,2-Dibromoethane (0.03 mL, 0.3 mmol). The resulting mixture was stirred under reflux for 15 min and then cooled to rt. To the reaction mixture was added TMSCl (0.03 mL, 0.2 mmol) and THF (5 mL). A solution of propargyl bromide (0.750 mL, 8.42 mmol) and THF (3 mL) was then added dropwise to the reaction mixture over a 30 min period at −10° C. After 1 h, 2,6-Dichlorobenzaldehyde (1.46 g, 8.33 mmol) was added to the reaction mixture and allowed to warm to rt and stirred for 36 h. The reaction mixture was quenched with 1 M aqueous HCl (15 mL) and the organic layer was washed with brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield a dark yellow oil. The crude product was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to yield the desired product as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ=2.03-2.06 (m, 1H), 2.82-2.90 (m, 1H), 3.00-3.07 (m, 1H), 3.09 (d, J=9.1 Hz, 1H), 5.67 (td, J=8.8, 6.6 Hz, 1H), 7.14-7.21 (m, 1H), 7.32 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[N:22]#[C:23][NH2:24].[F:25][C:26]([F:32])([F:31])[S:27]([OH:30])(=[O:29])=[O:28]>C1COCC1>[OH:30][S:27]([C:26]([F:32])([F:31])[F:25])(=[O:29])=[O:28].[C:23](=[NH:22])([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:18]([F:19])([F:20])[F:21])[CH:4]=2)=[CH:14][CH:13]=1)[NH2:24]
Reactant: N#CN
Reactant: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 55 °C
Yield: 62.7 %

Procedure:
To a solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethanol (2.63 g, 8.30 mmol) and cyanamide (0.419 g, 9.97 mmol) in dry THF (25 mL) under argon was added trifluoromethanesulfonic acid (0.885 mL, 9.97 mmol). The mixture was heated to 55° C. for 3 hrs. Purification via a reverse phase biotage with TFA then afforded the title compound (2.65 g, 62.8% yield). LCMS: rt=2.906 min, [M+H+]=359
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.Br[CH2:10][C:11]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[O:12]1>CN(C=O)C.O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[O:12][C:11]1([CH2:10][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[I:3])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: Ic1ncc[nH]1
Reactant: Fc1ccc(C2(CBr)OC2c2ccccc2Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(C2(Cn3ccnc3I)OC2c2ccccc2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
At 3° C., sodium hydride (60% by weight strength dispersion in mineral oil, 56.7 mg, 1.41 mmol) was added to a stirred solution of 2-iodoimidazole (242 mg, 1.25 mmol) in dry DMF (8 ml). The reaction mixture was stirred at room temperature for 20 min, and 2-(bromomethyl)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxirane (300 mg, 0.83 mmol) in dry DMF (4 ml) was then added. The resulting mixture was stirred at 50° C. for 20 h and then at 80° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with AcOEt, and the extracts were dried and concentrated to dryness under reduced pressure. The filtrates were combined and concentrated to dryness under reduced pressure. Purification of the residue on silica gel gave 1-{[3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-2-iodo-1H-imidazole as a 55/45 mixture of diastereoisomers [298 mg, colourless solid, yield 72%; HPLC/MS: m/z=473 (M+H); log P(HCOOH)=2.92 (major diastereoisomer), 3.31 (minor diastereoisomer)].
Reaction SMILES: FC(F)(F)C(O)=O.C(N)CN.[F:12][C:13]([F:54])([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C@H:14]([NH:16][C:17]([C:19]1[C:27]2[C:22](=[N:23][CH:24]=[C:25]([C:28]3[C:36]4[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=4)[N:30]([CH3:38])[N:29]=3)[N:26]=2)[N:21](COCC[Si](C)(C)C)[CH:20]=1)=[O:18])[CH3:15]>ClCCl>[F:54][C:13]([F:12])([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C@H:14]([NH:16][C:17]([C:19]1[C:27]2[C:22](=[N:23][CH:24]=[C:25]([C:28]3[C:36]4[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=4)[N:30]([CH3:38])[N:29]=3)[N:26]=2)[NH:21][CH:20]=1)=[O:18])[CH3:15]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(F)(F)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(F)(F)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2,2-difluoro-1-methyl-3-phenyl-propyl)-amide (133 mg, 0.21 mmol was dissolved in dichloromethane (1.1 ml) and trifluoroacetic acid (0.64 ml, 8.3 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1.1 ml) and ethylenediamine (0.84 ml, 12.4 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with 5% EtOAc/diethyl ether to afford 73 mg (70%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2,2-difluoro-1-methyl-3-phenyl-propyl)-amide as a light yellow powder. MS: (M+Na)+=501; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.94 (br. s., 1H), 9.12 (s, 1H), 8.52 (s, 1H), 8.47 (dd, J=8.9, 5.4 Hz, 1H), 8.36 (d, J=9.8 Hz, 1H), 7.68 (dd, J=9.8, 2.0 Hz, 1H), 7.23-7.35 (m, 5H), 7.02 (td, J=9.0, 2.3 Hz, 1H), 4.60-4.78 (m, 1H), 4.15 (s, 3H), 3.33-3.45 (m, 2H), 1.41 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27]>>[CH2:26]([S:28]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:30])=[O:29])[CH3:27]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 7.6 μL (0.11 mmol) ethanesulfonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(O)C[OH:30].O.C(OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([O:25][CH2:26][CH2:27][OH:30])=[O:24]
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Reactant: OCCO
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)OCCO
Reaction time: 50 h

Procedure:
A mixture of ethyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (2 g) and ethyleneglycol (8 ml) was stirred for 50 hours at 90°. The reaction mixture was poured into a mixture of water (50 ml), ethyl acetate (50 ml) and tetrahydrofuran (50 ml). The solvent was distilled off. The residue was chromatographed on silica gel, eluting with a mixture of n-hexane and ethyl acetate (10:1). The fractions containing the object compound were combined and concentrated in vacuo. The crystalline residue was recrystallized from diethyl ether to afford 2-hydroxyethyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate.
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][C:6]21[O:10][CH:9]([CH2:11][CH3:12])[CH2:8][O:7]2)([CH3:4])([CH3:3])[CH3:2].C(C1CCCCC1=O)(C)(C)C.C(O)C(O)CC>[Pd].C(O)(C)C>[C:1]([CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:6]1[O:7][CH2:8][CH:9]([OH:10])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1COC2(CCCCC2C(C)(C)C)O1
Agent: [Pd]
Agent: CC(C)(C)C1CCCCC1=O
Agent: CCC(O)CO
Solvent: CC(C)O
Product: CCC(O)COC1CCCCC1C(C)(C)C
Yield: 81.5 %

Procedure:
A 500 ml capacity autoclave was charged with 30 g (0.13 mol) of 6-t-butyl-2-ethyl-1,4-dioxaspiro[4.5]decane which has been prepared from 2-t-butylcyclohexanone and 1,2-butanediol, 150 g of isopropanol and 0.3 g of a catalyst of 5% palladium supported on active carbon (pH=7.6). The reaction was carried out under a hydrogen pressure of 70 kg/cm2 and at a temperature of 190° C. for 20 hours until completion of the absorption of hydrogen. After the reaction, the catalyst was removed by filtration and the resulting filtrate was subjected to distillation to obtain 24.2 g of 1-(2-t-butylcyclohexyloxy)-2-butanol (b.p.=122° to123° C./5 mmHg; yield=80%; cis:trans=66:34).
Reaction SMILES: [CH2:1]([C:4]1[CH:22]=[C:21]([CH2:23]O)[CH:20]=[C:19]([CH2:25][CH2:26][CH3:27])[C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH3:3].P(Br)(Br)[Br:29].Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:4]1[CH:22]=[C:21]([CH2:23][Br:29])[CH:20]=[C:19]([CH2:25][CH2:26][CH3:27])[C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH3:3]
Reactant: BrP(Br)Br
Reactant: CCCc1cc(CO)cc(CCC)c1OC(C(=O)OC)c1cccc(Cl)c1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1cccc(Cl)c1

Procedure:
To a solution of 1.133 g (0.29 mmol) of the product of Step B dissolved in 10 mL of carbon tetrachloride was added 0.138 mL (1.45 mmol) of phosphorous tribromide and the reaction mixture was magnetically stirred at room temperature for 30 min as hydrogen bromide was evolved. The magnetic stir bar was removed, and the reaction mixture was concentrated in vacuo. The residue was redissolved and evaporated from carbon tetrachloride several times to remove most of the hydrogen bromide. Finally, the residue was purified by rapid flash chromatography on a silica gel column eluted with 10% EtOAc-hexane. Combination and evaporation of the purified fractions in vacuo afforded 1.063 (81%) of the title compound.