Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=[CH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][C:25]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[CH2:24][CH2:23]3)[C:12]3[C:13]([O:18][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[N:14][CH:15]=[CH:16][CH:17]=3)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:42](I)[CH2:43][CH3:44]>CN(C=O)C.C(OCC)(=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH:19]=[C:11]3[C:12]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[O:18][C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([O:3][CH2:42][CH2:43][CH3:44])=[O:2])[C:9]=4[CH2:10]3)[CH2:23][CH2:24]2)=[CH:34][CH:33]=1
Reactant: O=C(O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 55 °C
Yield: 87.8 %

Procedure:
To a solution of the compound of Example 118 (109 mg, 0.22 mmol) in dry DMF (5 ml) was added potassium carbonate (91 mg) followed by propyl iodide (24 μL, 0.66 mmol). The mixture was heated to 55° C. for 14 hours. The mixture was diluted with ethyl acetate (200 ml), washed twice with water (200 ml) and then with brine (100 ml), and dried with sodium sulfate. The organic solvent was removed under reduced pressure and the residue subjected to silica gel chromatography using a dichloromethane:methanol gradient (0 to 5% MeOH over 1 hour) to give the title compound (103 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:28]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Reactant: O=S(=O)(NCCO)c1ccccc1Br
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccccc2S(=O)(=O)NCCO)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-bromo-N-(2-hydroxyethyl)benzenesulfonamide. MS (ESI): mass calcd. for C19H16FNO53S, 413.10; m/z found, 414.0 [M+H]+. 1H NMR (500 MHz, DMSO-δ6) δ 8.26 (s, 1H), 7.99 (dd, J=7.9, 1.4, 1H), 7.72-7.59 (m, 3H), 7.47-7.41 (m, 2H), 7.41-7.31 (m, 4H), 4.70-4.64 (t, J=5.5, 1H), 3.45-3.27 (m, 2H), 2.85-2.78 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[O:22]C)[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[CH3:18])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[O:7][C:6]1[CH:19]=[CH:20][C:21]([OH:22])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene (500 mg, 1.59 mmol) in CH2Cl2 (12 mL was added boron tribromide (1 M in CH2Cl2, 3.2 mL, 3.2 mmol). The resulting mixture was stirred 1 h at RT then quenched with water (15 mL) and 1 M HCL (10 mL). After stirring 30 min at RT, the solution was extracted with CH2Cl2 (3×20 mL). Combined extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound of Step B. The title product of Step B was used in the next step without further purification. MS (APCl−) Calc.: 301. Found: 300.2 (M−1).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: C1=COCCC1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)c1ccccc1n2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a stirred solution of carbazole (20.0 gm, 0.119 moles) in dry chloroform (300 ml) at 0° C., D-10 camphor sulphonic acid (5% W/W, 1.0 gm) was added followed by a solution of 3,4-dihydro 2H-pyran (0.149 moles, 13.6 ml) in dry chloroform (50 ml) dropwise over a period of 30 min. The reaction mixture was gradually warmed to room temperature and stirred at the same temperature for 2 hours. The reaction mixture was diluted with chloroform (400 ml) and washed with a solution of saturated NaHCO3 (150 ml), followed by water (150 ml), dried over Na2SO4 and concentrated to give 31 gm of crude material which was recrystallised from 500 ml of iso-propanol to give 24 gm of the title product as white crystalline powder, m. p: 131-133° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[N:40](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:5]([C:12]([O:14][CH2:15][C:16]2[O:17][C:18](=[O:22])[O:19][C:20]=2[CH3:21])=[O:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:7]=1)[CH3:2]>C(O)(=O)C>[CH2:1]([C:3]1[N:4]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:5]([C:12]([O:14][CH2:15][C:16]2[O:17][C:18](=[O:22])[O:19][C:20]=2[CH3:21])=[O:13])=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 93.5 %

Procedure:
Following a procedure similar to that described in Example 78(b), but using 1.90 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] and 20 ml of 75% v/v aqueous acetic acid, 1.23 g of the title compound was obtained as a crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][N:9]=1)=[O:7])[CH3:2].C(OC(=O)C(C(C1C(F)=CC=CN=1)=O)=[CH:21][N:22]([CH3:24])[CH3:23])C>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:6]([C:8]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][N:9]=1)=[O:7])=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1nccnc1Cl
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ncccc1F
Product: CCOC(=O)C(=CN(C)C)C(=O)c1nccnc1Cl

Procedure:
2-(3-Chloro-pyrazine-2-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (13) (1.2 g, crude) was synthesized as a sticky liquid from 1 g of 3-(3-chloro-pyrazin-2-yl)-3-oxo-propionic acid ethyl ester (12) following the procedure described for 3-dimethylamino-2-(3-fluoro-pyridine-2-carbonyl)-acrylic acid ethyl ester (4).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:8])=[N:5][S:6][CH:7]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].[BrH:14]>>[BrH:14].[CH3:8][C:4]1[C:3]([CH2:2][S:13][CH2:12][CH2:11][NH2:10])=[CH:7][S:6][N:5]=1
Reactant: Cc1nscc1CO
Reactant: NCCS
Agent: Br
Agent: Cl
Product: Cc1nscc1CSCCN

Procedure:
Reacting 4-hydroxymethyl-3-methylisothiazole (3.0 g) with cysteamine hydrochloride (2.8 g) in 48% aqueous hydrobromic acid (50 ml) by the procedure of Example 58 gives 3-methyl-4-[(2-aminoethyl)thiomethyl]-isothiazole hydrobromide. Treatment of this intermediate with aqueous potassium carbonate, extracting with chloroform, drying the chloroform extract over magnesium sulphate and concentrating gives the free base, 5.0 g. of which is then reacted with methyl isothiocyanate (1.94 g) in ethanol (25 ml) under reflux for 30 minutes. The product is purified on a column of alumina and elution with benzene gives N-methyl-N'-[2-((3-methyl-4-isothiazolyl)methylthio)ethyl]thiourea. Reaction of this product by the procedure of Example 91 gives N-cyano-N'-methyl-N"-[2-((3-methyl-4-isothiazolyl)-methylthio)ethyl]guanidine.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C@@H:8]1[CH2:12][CH2:11][O:10][CH2:9]1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20].Cl>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:7][C@@H:8]4[CH2:12][CH2:11][O:10][CH2:9]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: O[C@@H]1CCOC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@@H]1CCOC1
Reaction time: 1 h

Procedure:
13.80 g of potassium tert-butoxide are added batchwise to a solution of 10.80 g of (R)-3-hydroxytetrahydrofuran in 100 ml of N,N-dimethylformamide while cooling with an ice bath. The reaction mixture is stirred for about one hour, then 10.40 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-fluoroquinazoline are added batchwise. The cooling bath is then removed and the deep red reaction mixture is stirred for two hours at ambient temperature. For working up the reaction mixture is poured onto about 500 ml of water and neutralized with 2 N hydrochloric acid. The yellowish precipitate formed is suction filtered and dried at 70° C. in a circulating air drier. Yield: 12.80 g; melting point: 244° C.; mass spectrum (ESI−): m/z=403, 405 [M−H]−.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[IH:33]>C(OCC)(=O)C>[IH:33].[IH:33].[N:11]1([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:24])[F:25])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCC(F)(F)F)CC1
Agent: I
Solvent: CO
Solvent: CCOC(C)=O
Product: FC(F)(F)CCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Treat a solution of 4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.80 g, 4.22 mmol) and methanol (15 mL) at 0° C. with 57% hydroiodic acid (3.79 g, 16.9 mmol). Stir at room temperature for 30 minutes, heat to 50° C. for two hours and then stir at room temperature overnight. Thin layer analysis (silica gel, ethyl acetate) indicates the presence of starting material. Add 57% hydroiodic acid (1.12 mL) and heat at 50° C. for two hours. Concentrate in vacuo to remove the methanol, dissolve the residue in methanol (10 mL) and add ether (total of 200 mL) to afford a white tacky precipitate. Decant the supernatant, add ether (200 mL) and stir to afford a cream colored solid. Collect the solid by vacuum filtration under nitrogen and dry in vacuo at 82° C. (0.2 Torr) overnight to afford 2.25 g of 2-[1,4]diazepan-1-yl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole dihydroiodide, m.p. 206-208° C. Elemental Analysis: Calculated for C16H21F3N4.2HI: 33.01%C, 3.98%H, 9.62%N; Found 33.15%C, 3.87%H, 9.41%N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CC[N:15]([CH:19]([CH3:21])[CH3:20])C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1(N)CC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:15][CH:19]2[CH2:21][CH2:20]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)NC1CC1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 18.0 g (79.0 mmol) 2-(4-bromo-phenyl)-propionic acid (Bioorg. Med. Chem. Lett. 2010, 20, 887) and 68.4 mL (393 mmol) DIPEA in 90 mL DMF, 50.5 g (157 mmol) TBTU are added. The mixture is stirred for 15 min at 0° C. After that time, 16.3 mL (236 mmol) cyclopropylamine are added and the mixture is stirred for 16 h at rt. After that time, iced water is added and the mixture is extracted with EtOAc. The organic layer is washed with brine and dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel; hexane/EtOAc 7:3) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)[N:20]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][C:16]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([C:21]4[N:20]=[N:19][CH:24]=[CH:23][CH:22]=4)=[CH:30][N:29]=3)=[O:18])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2cccnn2)cn1
Reactant: Cc1cc(CC(=O)O)cnc1-c1ccnc(F)c1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: Cc1cc(CC(=O)Nc2ccc(-c3cccnn3)cn2)cnc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the mixture of 2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)acetic acid 193-2 (25 mg, 0.1 mmol) and 5-(pyridazin-3-yl)pyridin-2-amine 145-3 (17 mg, 0.1 mmol) in DCM (1 mL) was added N,N′-Diisopropylcarbodiimide (22 μL, 0.15 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours. The solvent was removed by rotary evaporation and the residue was dissolved in DMSO and then purified by reverse-phase HPLC to give 2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 221 as white solid. MS m/z 401.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.09 (s, 1H), 9.17 (dd, 1H), 9.07 (d, 1H), 8.51 (dd, 1H), 8.46 (d, 1H), 8.28 (d, 1H), 8.25 (dd, 1H), 8.18 (d, 1H), 7.76 (m, 1H), 7.71 (d, 1H), 7.51 (m, 1H), 7.31 (s, 1H), 3.83 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]Cl.[SH:14][CH2:15][CH2:16][S:17][CH2:18][CH2:19][SH:20].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:10]1[CH2:11][CH2:12][S:20][CH2:19][CH2:18][S:17][CH2:16][CH2:15][S:14][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: SCCSCCS
Reactant: ClCCOCCOCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C1COCCSCCSCCSCCOCCO1

Procedure:
This compound is obtained by reacting 1,11-dichloro-3,6,9-trioxaundecane with 1,5-dimercapto-3-thiapentane in the presence of sodium carbonate in aqueous ethanol: ##STR8##
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[C:25]([OH:28])(=[O:27])[CH3:26]>>[C:25]([O:28][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])(=[O:27])[CH3:26]
Reactant: CC(=O)O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Product: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (500 mg.) was dissolved in glacial acetic acid (25 ml.), and the solution was heated on a steam-bath for 3 hours. Evaporation of the solution under reduced pressure gave an oil which was purified by preparative TLC in ethyl acetate-petrol, and foamed in vacuo to give the title compound as a white foam, [α]D + 93.5°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[NH:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]=2)[CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+].COCCOC>O>[CH2:25]([NH:24][C:23]1[CH:22]=[C:21]([CH3:27])[NH:20][C:19](=[O:28])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:39]2[CH:38]=[N:37][C:36]([N:33]3[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]3)=[CH:41][CH:40]=2)[CH:3]=1)=[O:15])[CH3:26]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCNc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCNc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc2c1ccn2C(C)C
Temperature: 85 °C
Yield: 59.4 %

Procedure:
To a 20 mL microwave vial was added 6-bromo-N-{[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-1H-indole-4-carboxamide (70 mg, 0.170 mmol), and 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (59.9 mg, 0.198 mmol). PdCl2(dppf)-CH2C12 adduct (14.67 mg, 0.018 mmol) and sodium bicarbonate (45.3 mg, 0.539 mmol) were added followed by 1,2-Dimethoxyethane (DME) (5 mL) and Water (2 mL). The vial was sealed and the reaction was heated to 85° C. for 1 hr. The reaction was cooled and evaporated. The material was taken into Methanol/DMSO and was filtered through an acrodisk and purified by reverse phase Gilson HPLC (5-80% acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column, 6 minutes) the desired fractions were collected and evaporated from 0.1N NaOH which provided the desired product N-{[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide (57 mg, 0.101 mmol, 56.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (s, 1H) 8.89 (t, J=5.94 Hz, 1H) 8.66 (d, J=2.02 Hz, 1H) 8.09 (dd, J=8.59, 2.02 Hz, 1H) 7.91 (s, 1H) 7.80 (s, 1H) 7.60 (d, J=3.03 Hz, 1H) 6.99 (d, J=8.84 Hz, 1H) 6.89-6.96 (m, 2H) 5.66 (s, 1H) 4.85-4.98 (m, 1H) 4.39 (d, J=5.81 Hz, 2H) 3.63 (br. s., 4H) 3.11-3.24 (m, 2H) 2.7 (bs, 4H) 2.08 (s, 3H) 1.47 (d, J=6.57 Hz, 6H) 1.20 (t, 3H). MS(ES) [M+H]+ 542.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:20])[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:20][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[N:30][C:22]=3[CH3:21])[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Reactant: Cc1ncccc1C(=O)O
Product: Cc1ncccc1C(=O)Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Yield: 40 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-cyclopropylmethoxy-9H-β-carbolin-8-ylamine and 2-methylnicotinic acid in a 40-60% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:10]1[NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH3:8].C(O)(=O)C.O.[OH-].[NH4+]>[Pd].C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[NH:11][C:12](=[O:21])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[CH3:8]
Reactant: COc1ccc(C(=O)NC2C=CC=CC2=C(C)c2ccccn2)cc1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2C(C)c2ccccn2)cc1

Procedure:
2'-[1-(2-Pyridyl)-ethylidene]-p-anisanilide (6.0 g., 0.018 mole) is reduced in a Parr apparatus in 100 ml. of acetic acid employing 1.0 g. of 10% palladium on carbon catalyst. The catalyst is collected, the filtrate concentrated under reduced pressure and the residue thus obtained distributed between water and ethyl acetate. This mixture is made basic with concentrated ammonium hydroxide and the ethyl acetate extract separated, dried, and concentrated to provide 2'-1-(2-pyridyl)ethyl-p-anisanilide, m.p. 125°-126° C. (corr.), from aqueous ethanol.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([CH2:17][CH3:18])[C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:25]#[C:26]Br.C(OC(=O)C)C>C1COCC1.O>[NH2:25][C:26]1[O:4][CH2:3][C@H:2]([CH2:5][N:6]([CH2:17][CH3:18])[C:7]2[CH:8]=[N:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)[N:1]=1
Reactant: N#CBr
Reactant: CCN(C[C@H](N)CO)c1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCN(C[C@H]1COC(N)=N1)c1ccc(C(F)(F)F)nc1
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a stirred mixture of (S)-2-amino-3-[ethyl-(6-trifluoromethyl-pyridin-3-yl)-amino]-propan-1-ol (0.04 g, 0.15 mmol) and K2CO3 (0.025 g, 0.18 mmol) in THF (2 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.025 g, 0.18 mmol) in THF (1 ml). The mixture was stirred for 1 hour, then ethylacetate and water were added. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, EtOAc/MeOH=9:1) to give the title compound as white solid (0.02 g, 46%), MS (ISP): 289.0 ([M+H]+).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[N:12]=[C:11](Cl)[C:10]([CH:14]=O)=[C:9]([Cl:16])[N:8]=1.Cl.[NH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:19]>C(N(CC)CC)C>[Cl:16][C:9]1[N:8]=[C:7]([Cl:6])[N:12]=[C:11]2[N:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=[CH:14][C:10]=12
Reactant: CCOC(=O)CNN
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ncc2c(Cl)nc(Cl)nc21
Temperature: 10 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
155 ml of THF are added with stirring to a mixture of 5.17 g of 2,4,6-tri-chloropyrimidine-5-carbaldehyde and 5.85 g of ethyl hydrazinoacetate hydrochloride. The mixture is cooled to 10° C., and 6.78 ml of triethylamine are added dropwise. The mixture is stirred at RT for a further 1 h. The deposited precipitate is separated off (not the product). The filtrate, which contains the product, is subjected to conventional work-up, giving 3 g of ethyl (4,6-dichloropyrazolo[3,4-d]pyrimidin-1-yl)acetate (“12”).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:51]=[CH:50][CH:49]=[CH:48][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[C:20]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([CH:35]4[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]4)=[N:33][CH:34]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[NH:38]1[CH2:37][CH2:36][CH:35]([C:32]2[N:33]=[CH:34][C:29]([NH:28][C:20]3[N:19]=[C:18]([CH2:17][CH2:16][C:15]4[CH:48]=[CH:49][CH:50]=[CH:51][C:14]=4[C:11]4([C:8]([NH2:9])=[O:10])[CH2:12][CH2:13]4)[C:23]([C:24]([F:26])([F:25])[F:27])=[CH:22][N:21]=3)=[CH:30][CH:31]=2)[CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)nc3)ncc2C(F)(F)F)CC1
Reaction time: 4 h

Procedure:
TFA (0.50 mL, 6.5 mmol) was added to a mixture of tert-Butyl 4-(5-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A79 (0.080 g, 0.13 mmol) in DCM (5 mL) and the mixture stirred for 4 hours. The mixture was concentrated under reduced pressure and quenched with 25% aqueous NaOH (20 mL) before extracting with EtOAc (3×20 mL). The combined organic extracts were concentrated under reduced pressure and the above procedure repeated with DCM (1.5 mL) and TFA (0.2 mL) for 3 hours. The mixture was concentrated under reduced pressure and quenched with 25% aqueous NaOH (20 mL) before extracting with EtOAc (3×20 mL). The combined organic residues were dried (phase separation cartridge) and concentrated under reduced pressure to give the title compound 68 (0.069 g, quantitative). LCMS-A: rt 4.783 min; m/z 511.3 [M+H]+.