Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([C:18](=[O:31])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)C>[Pd].O1CCCC1>[CH3:1][O:2][CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([C:18](=[O:31])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OC
Reaction time: 7.5 h
Yield: 95.1 %

Procedure:
Ethyl 2-methoxy-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]acrylate (150 mg, 0.354 mmol), 2.5 ml of ethanol and 2.5 ml of tetrahydrofuran were mixed, 10% palladium on activated carbon (30 mg) was added thereto, and normal pressure hydrogenation was conducted for 7.5 hours at room temperature. After completion of the reaction, the catalyst was filtered and the filtrate was concentrated to obtain 148 mg (98%) of the title compound as colorless crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=1)([CH3:3])[CH3:2].CO[CH:31](OC)[CH2:32][NH2:33].C(C1C=C(C2C=CC=CC=2)C=C(C(C)C)C=1N1C=CN=C1C1C=CC=C(OC)C=1)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9]=1[N:10]1[CH:31]=[CH:32][N:33]=[C:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=1)([CH3:3])[CH3:2]
Reactant: COC(CN)OC
Reactant: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1NC(=O)c1cccc(I)c1
Agent: COc1cccc(-c2nccn2-c2c(C(C)C)cc(-c3ccccc3)cc2C(C)C)c1
Product: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1-n1ccnc1-c1cccc(I)c1

Procedure:
The title compound was prepared from N-(3,5-diisopropyl-[1,1′-biphenyl]-4-yl)-3-iodobenzamide and 2,2-dimethoxyethanamine in substantially the same manner, as described in Synthesis of 1-(3,5-diisopropyl-[1,1′-biphenyl]-4-yl)-2-(3-methoxyphenyl)-1H-imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.1 %

Procedure:
2-Bromophenol (1.22 mL, 11.6 mmol), phenylboronic acid (2.8 g, 23.1 mmol), Cu(OAc)2 (4.2 g, 23.1 mmol) and pyridine (4.66 mL, 57.8 mmol) were dissolved in dichloromethane (100 mL) in a reaction vessel holding 1 g of 4 Å M.S. and stirred at room temperature for 18 hours. After the reaction was completed, the reaction mixture was diluted with dichloromethane and filtered through Celite. The filtrate was extracted with 1 N NaOH and brine, and the organic layer was dried with anhydrous MgSO4 and filtered again. The filtrate was concentrated under reduced pressure) to obtain 436 mg of the target compound (1.75 mmol, 15.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[S:17]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:22]([C:19]1[CH:20]=[CH:21][S:17][CH:18]=1)(=[O:24])=[O:23])[CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1ccc2[nH]cc(CCC(=O)O)c2c1
Reactant: O=S(=O)(Cl)c1ccsc1
Product: COc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccsc1

Procedure:
3-[5-Methoxy-1-(thiophene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 99 was prepared from 3-(5-methoxy-1H-indol-3-yl)-propionic acid 96 and 3-thienyl-sulfonyl chloride using the same protocol as described in step 8, Example 4. (M−1, 364.4)
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[N:10]=1)(=O)=O.CN1C(=O)CCC1.[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH2:40])[CH3:36].O>CCOC(C)=O>[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH:40][C:5]1[N:6]=[C:7]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[N:10]=1)[CH3:36]
Reactant: CCN(CC)CCN
Reactant: CS(=O)(=O)c1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCN(CC)CCNc1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A solution of the product of Example 46 (18.8 mg, 0.05 mmol), NMP (5 mL) and N,N-diethylethylenediamine (28 mg, 0.25 mmol, 5 eq) was heated to 50°. After 1 h, H2O (20 mL) was added and then EtOAc (20 mL). The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4) filtered and the solvent was evaporated in vacuo. The yellow residue was purified by Flash chromatography to afford 2-(2-diethylamino-ethylamino)-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one (21 mg, 89% yield). 1H-NMR (CDCl3) δ 0.74-0.98 (m, 6H), 2.28-2.56 (m, 8H), 2.98 (br s, 1H), 6.32 (d, 1H, J=9.8 Hz), 7.26 (m, 2H), 7.09-7.88 (m, 1111), LC MS (m/e)=414 (MH+).
Reaction SMILES: C([O:5][C:6]1[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][N:7]=1)CCC.O>C(O)C>[C:13]1([C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH2:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOC1=NC=CC(c2ccccc2)=CC1
Solvent: O
Solvent: CCO
Product: O=C1CC=C(c2ccccc2)C=CN1
Temperature: 150 °C
Yield: 88.2 %

Procedure:
The 2-butoxy-5-phenyl-3H-azepine (908 g, 3.42 moles) is dissolved in 2B-3 ethanol (8172 mL) and de-ionized water (2724 mL). The solution is charged to an autoclave and heated to 150° C. for 20 hours. The solution is cooled to room temperature and concentrated under reduced pressure. Residual water is removed by azeotropic distillation from toluene (2×2 L). The residual solids are dissolved in toluene (1.7 L) and heated between 95 to 100° C. The solution is cooled to <90° C. and heptane (about 4.8 mL/g) is added. The solution is allowed to cool to room temperature, and then cooled to 0 to 5° C. using an ice bath. The solids are filtered, washed with heptane, and dried to give the title compound (559 g, 88%) as a light brown solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]1[CH2:12][CH:11]2[CH2:13][CH:4]1[C:5]1[CH:10]2[CH2:9][CH2:8][CH2:7][CH:6]=1.[H][H]>[Pd].CO>[F:1][C:2]([F:14])([F:15])[CH:3]1[CH2:12][CH:11]2[CH2:13][CH:4]1[CH:5]1[CH:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: FC(F)(F)C1CC2CC1C1=CCCCC12
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)C1CC2CC1C1CCCCC21
Reaction time: 0.75 h

Procedure:
A 400 ml autoclave is charged with 177 g of the thus purified octahydro-2-trifluormethyl-1,4-methanonaphthalene, methanol (100 ml, Burdick & Jackson, HPLC grade), and palladium on activated carbon (1.5 g containing 10% Pd, Alfa products, powder). The autoclave is closed and sealed, then it is shaken under 50 psig hydrogen pressure for 20 minutes at room temperature. The hydrogen pressure is increased to 200 psig for 10 minutes at room temperature followed by 600 psig at 70° C. for 45 minutes. The decahydro-2-trifluormethyl-1,4-methanonaphthalene product is purified by distillation at reduced pressure. The distilled product is then treated with concentrated sulfuric acid followed by silica gel treatment similar to what described in the example 2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNCC
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CCN(CC)S(=O)(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of 50% aqueous diethylamine. The mixture is stirred at room temperature for 4 hours, cooled, and the precipitated 4-acetyl-N,N-diethylbenzenesulfonamide removed by filtration, washed with water and dried; m.p. 78°-79° C. after crystallization from 2-propanol.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:5][C:6]=1[C:7]#[N:8].C([OH:24])CC.[OH-].[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[S:3][C:4]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:5][C:6]=1[C:7]([NH2:8])=[O:24]
Reactant: CCCO
Reactant: N#Cc1cc(-c2ccc(N3CCCCC3)nc2)sc1N
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(-c2ccc(N3CCCCC3)nc2)sc1N
Temperature: 130 °C

Procedure:
Into a microwave vial was added 2-amino-5-(6-piperidin-1-ylpyridin-3-yl)thiophene-3-carbonitrile (225 mg, 0.79 mmol), 1-propanol (6.2 ml), and 25% sodium hydroxide (1.8 ml) and the mixture was heated in the microwave to 130° C. for 30 min. The reaction mixture was diluted with ethyl acetate and sodium bicarbonate to neutralize, extracted with ethyl acetate (3×100 mL), dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/methanol to afford the title compound as a solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]([Cl:15])([Cl:14])[C:7]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)=[O:8]>C(OC(=O)C)(=O)C>[Cl:15][C:6]([Cl:5])([Cl:14])[C:7]([C:9]1[NH:10][CH:11]=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=1)=[O:8]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: O=C(c1cc([N+](=O)[O-])c[nH]1)C(Cl)(Cl)Cl
Temperature: -40 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
Nitric acid (90%, 2 mL) was added dropwise over a period of 30 minutes to a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl) ethanone (II) (1 g, 4.7 mmol) in acetic anhydride (10 ml), cooled to −40° C. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 6 h. The solvent was evaporated under vacuum and the residue purified by flash chromatography (hexane-EtOAc 9:1) to obtain the compound of formula (III) as a yellow solid (670 mg, 55% yield). 2,2,2-Trichloro-1-(5-nitro-1H-pyrrol-2-yl)ethanone was also obtained as side product (349 mg, 29% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[N:4][CH:3]=1.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([N:19]3[CH:20]=[CH:21][N:22]=[C:18]3[CH3:17])[N:7]=2)=[CH:11][CH:12]=1
Reactant: Cc1ncc[nH]1
Reactant: Fc1ccc(CNc2cncc(Cl)n2)cc1
Product: Cc1nccn1-c1cncc(NCc2ccc(F)cc2)n1
Yield: 23.5 %

Procedure:
In a procedure analogous to example 2, reaction of 6-chloro-N-(4-fluorobenzyl)pyrazin-2-amine (150 mg, 0.63 mmol) and 2-methylimidazole (57 mg, 0.69 mmol) furnished the product (42 mg, 23%).
Reaction SMILES: [N:1]1([CH2:5][C@@H:6]([N:10]([CH3:20])[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1.[C:21]([OH:30])(=[O:29])[CH:22]([CH:24]([C:26]([OH:28])=[O:27])[OH:25])[OH:23]>CC#N.O>[OH:25][CH:24]([CH:22]([OH:23])[C:21]([O-:30])=[O:29])[C:26]([O-:28])=[O:27].[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([N:10]([C@@H:6]([CH:7]([CH3:8])[CH3:9])[CH2:5][NH+:1]2[CH2:4][CH2:3][CH2:2]2)[CH3:20])=[O:19])=[CH:17][CH:16]=1.[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([N:10]([C@@H:6]([CH:7]([CH3:8])[CH3:9])[CH2:5][NH+:1]2[CH2:4][CH2:3][CH2:2]2)[CH3:20])=[O:19])=[CH:17][CH:16]=1
Reactant: CC(C)[C@@H](CN1CCC1)N(C)C(=O)c1ccc(Cl)cc1
Reactant: O=C(O)C(O)C(O)C(=O)O
Solvent: O
Solvent: CC#N
Product: CC(C)[C@@H](C[NH+]1CCC1)N(C)C(=O)c1ccc(Cl)cc1
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Yield: 66 %

Procedure:
The title compound of Example 5.1 A was dissolved in MeCN (10 mL) and a solution of DL-tartaric acid (659 mg, 4.39 mmol) in water (15 mL) was added. The resulting mixture was filtered and the solution freeze dried in vacuo to give the title product (3.13 g, 66%). Mixture of rotamers: 1H NMR (400 MHz, DMSO-d6) δ 0.42-1.25, 1.52-1.86, 1.86-2.01, 2.01-2.24, 2.5-2.54, 2.64, 2.77, 2.84-3.23, 3.40-3.82, 3.95, 4.10-4.35, 7.10-7.71. Ratio major:minor:6:4. The compound was found to be amorphous by XRPD.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3].[Br:12]Br>ClCCl>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][Br:12])=[CH:5][CH:6]=1)#[N:11]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: BrBr
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)CBr)cc1
Yield: 101.5 %

Procedure:
To a solution of 4-cyanoacetophenone (11.32 g, 77.98 mmol) in dichloromethane (200 mL) was added bromine (4.00 mL, 78.0 mmol) dropwise at room temperature. After stirring several minutes, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 4-cyanophenacyl bromide (17.73 g) as a white solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][CH:8](O)[CH3:9].S(=O)(=O)(O)O>>[CH:8]([O:5][C:1](=[O:6])/[CH:2]=[CH:3]/[CH3:4])([CH3:9])[CH3:7]
Reactant: C/C=C/C(=O)O
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: C/C=C/C(=O)OC(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
Crotonic acid (193.7 g, 2.25 mol) was dissolved in 2-propanol (860 mL, 11.25 mol) in a 2 L flask and then well stirred, after which sulfuric acid (24 mL, 0.45 mol) was slowly added in droplets to the mixture and refluxed and stirred for 48 hours or longer. The stirred mixture was cooled to room temperature, after which the obtained mixture was washed with distilled water (1000 mL), and the organic layer was separated, neutralized and subjected to atmospheric distillation (80° C.), thus obtaining 220 g (1.71 mol, yield 76.3%) of crotonic acid isopropyl ester.
Reaction SMILES: [CH3:1][S:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](O)=[O:14])=[CH:10][CH:11]=2)[N:6]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][N:17]=2)[CH:5]=1)=[O:3].[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][C:29]1=[O:34]>>[CH3:1][S:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([N:31]3[CH2:32][CH2:33][NH:28][C:29](=[O:34])[CH2:30]3)=[O:14])=[CH:10][CH:11]=2)[N:6]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][N:17]=2)[CH:5]=1)=[O:3]
Reactant: O=C1CNCCN1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)O)ccc12
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCNC(=O)C3)ccc12

Procedure:
Synthesized from 3-(methylsulfinyl)-1-(5-phenylpyrimidin-2-yl)-1H-indole-6-carboxylic acid (200 mg, 0.53 mmol) and piperazin-2-one (64 mg, 0.63 mmol) in an analogous manner as described for example 52. White solid. Yield: 148 mg (61% of theory). HPLC-MS (method 4): Rt=2.6 min; m/z [M+H]+=460.3
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:29]=[CH:28][C:18]3[NH:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][CH2:23][C:17]=3[CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C-:30]#[N:31].[K+].[CH2:33]=O.[OH-].[Na+]>C(O)(=O)C.ClCCl>[C:30]([CH2:33][N:19]1[C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[CH2:22][CH2:23][C:17]2[CH:16]=[C:15]([CH2:14][N:13]3[C:6]4=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]4[N:4]=[C:3]3[CH2:1][CH3:2])[CH:29]=[CH:28][C:18]1=2)#[N:31]
Reactant: C=O
Reactant: [C-]#N
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2CC#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.8 %

Procedure:
[step 2] 2-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (55.4 g, 145 mmol) obtained in step 1 was dissolved in acetic acid (500 mL) and the solution was added with potassium cyanide (11 g, 169 mmol) and paraformaldehyde (4.6 g, 152 mmol) at 10° C., followed by stirring at room temperature for 24 hr. The mixture was added to a mixed solution of 10 mol/L aqueous sodium hydroxide solution (900 mL), ice (1 L) and dichloromethane (1 L). The organic layer was washed with 0.1 mol/L aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/triethylamine=10/10/1) to give 5-cyanomethyl-2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (39.0 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[N:38]1([CH2:44][C:45]([NH2:47])=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:39][CH2:40]3)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and 2-piperazin-1-yl-acetamide (Matrix) in an analogous manner as described in example 25. LR-MS: 681.2 [(M+H)+]
Reaction SMILES: [NH2:1][C:2]1([C:5]2[N:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]3=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=[CH:21][N:7]3[N:6]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[C:22]1([C:19]2[CH:20]=[CH:21][N:7]3[C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:5]([C:2]2([NH:1][C:35](=[O:36])[O:37][CH3:38])[CH2:3][CH2:4]2)=[N:6]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)Cl
Reactant: NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
To a stirred solution of 2-(1-aminocyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (60.0 mg, 0.168 mmol) in DCM (10 mL) was added pyridine (0.0270 mL, 0.337 mmol) followed by methyl chloroformate (0.0140 mL, 0.185 mmol) and the reaction mixture stirred at RT for 2 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed water (2×30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-93 as described in general methods) to give methyl (1-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (21.0 mg, 30.1%) as white solid. LCMS Condition B-34: retention time 2.29 min, [M+1]=415.0. HPLC Condition B-31: retention time 7.09 min, Purity 99.15%. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.06 (m, 2H), 1.34-1.41 (m, 2H), 3.54 (s, 3H), 4.67 (d, J=4.8 Hz, 2H), 6.68 (d, J=2.7 Hz, 1H), 7.00 (s, 1H), 7.27 (ddd, J=7.5 Hz, J=4.9 Hz, J=1.1 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.39-7.45 (m, 1H), 7.48-7.57 (m, 4H), 7.70 (d, J=2.7 Hz, 1H), 7.73-7.80 (m, 2H), 8.36-8.41 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O>[C:11]([NH:8][CH2:7][C:6]1[CH:15]=[C:2]([C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)[CH:3]=[C:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:5]=1[OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)NCc1cc(-c2ccncc2)cc(-c2ccccc2)c1O
Temperature: 55 °C
Yield: 32.4 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (from Example 42, Step 2) (0.404 g, 1.17 mmol), pyridin-4-ylboronic acid (0.288 g, 2.0 equiv), and potassium carbonate (0.647 g, 4 equiv) in isopropanol (30 mL) and water (6 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (88 mg, 6.5 mol %) was added and the resulting mixture was heated at 55° C. for 4 hours. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatograph to give 3-((tert-butylamino)methyl)-5-(pyridine-4-yl)-[1,1′-biphenyl]-2-ol (0.126 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][CH2:18][CH:19]=[CH2:20]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:20][CH2:19][CH:18]=[CH2:17])[CH:7]=1
Reactant: Oc1cc(Br)ccc1F
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCOc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-fluorophenol (19.63 g, 102.8 mmol) in DMF (410 mL) was added Cs2CO3 (40.19 g, 123.36 mmol, 1.2 eq.) followed by 4-bromo-1-butene (15.26 g, 11.48 mL, 113.06 mmol, 1.1 eq.). The mixture was stirred overnight at a temperature between 50 and 60° C. Then additional amounts of Cs2CO3 and the bromoalkene (20.1 g, 0.6 eq.) and (7.53 g, 5.74 mL, 0.55 eq.) respectively were added to the reaction mixture and heating was continued overnight. The mixture was cooled to room temperature and diluted with water. The aqueous mixture was extracted with EtOAc and the aqueous layer was separated and extracted once with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated onto 50 g Celite. Flash chromatography (SiO2, Hexanes to 30% EtOAc 70% Hexanes) provided 11.87 g, 47%, of the title compound as a colorless to light yellow oil.