Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C@H:4]1[CH2:7][C@H:6]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=[C:15]([I:18])[CH:16]=3)[C:11](=[O:23])[C:10]2=[O:24])[CH2:5]1)[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[Mg]I.C(=O)(O)[O-].[Na+]>O1CCCC1.CCOCC>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:11]1([OH:23])[C:12]2[C:17](=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[C:19]([F:21])([F:20])[F:22])[N:9]([CH2:8][C@H:6]2[CH2:5][C@H:4]([N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[CH2:7]2)[C:10]1=[O:24]
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(=O)c3c2cc(I)cc3C(F)(F)F)C1
Reactant: Clc1ccc([Mg]I)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 1-1 (3.13 g, 6.52 mmol) in tetrahydrofuran (65 mL) was added dropwise a solution of 2,4-dichlorophenylmagnesium iodide (9.78 mmol) in ether (19.6 mL) at −78° C. The mixture was stirred for 1 hour, and to the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=1/0 to 20/1 to 10/1 to 5/1) to give the titled compound (2.95 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[F:10][C:11]([F:18])([F:17])[C:12](OCC)=[O:13].C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:12](=[O:13])[C:11]([F:18])([F:17])[F:10]
Reactant: NCc1ccccc1Br
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NCc1ccccc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of 2-bromobenzylamine (1.3 mL, 10.8 mmol) in methanol (5 mL) was added ethyl trifluoroacetate (1.54 mL, 21.6 mmol) and triethylamine (1.4 mL, 10.8 mmol) under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction mixture was then concentrated under vacuum to yield N-(2-bromo-benzyl)-2,2,2-trifluoro-acetamide (3.15 g, quant.). HPLC ret. time 2.86 min, 10-99% CH3CN, 5 min run; ESI-MS 283.9 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:10]2)=[CH:5][CH:4]=1.Br.[CH3:26][O:27][C:28]([C:30]1[CH2:31][NH:32][CH2:33][CH2:34][CH:35]=1)=[O:29].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:26][O:27][C:28]([C:30]1[CH2:31][N:32]([CH2:13][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:33][CH2:34][CH:35]=1)=[O:29]
Reactant: COC(=O)C1=CCCNC1
Reactant: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)CC2
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=CCCN(CC2CCc3ccc(OC)cc3C2)C1
Reaction time: 18 h

Procedure:
To a solution of 5.19 g (15 mmol) of p-toluene-sulphonic acid (7-methoxy-1,2,3,4-tetrahydro-naphth-2-ylmethyl) ester in 75 ml of dimethylformamide there are added first 3.66 g (16.5 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 6.78 g (52.5 mmol) of N-ethyl-N,N-diisopropylamine. The mixture is stirred at 60° for 18 hours and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The organic phases are washed with water and extracted with 2N hydrochloric acid. The hydrochloric acid extracts are rendered alkaline at reduced temperature with sodium hydroxide solution (30%) and are extracted with dichloromethane, whereupon the combined organic phases are dried over sodium sulphate and concentrated by evaporation under reduced pressure. 1-[(7-methoxy-1,2,3,4-tetrahydro-naphth-2-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester is obtained in the form of a light-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:19])[CH3:18].C(=O)(O)[O-].[Na+]>CCO.C1COCC1>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17](=[O:19])[CH3:18])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(=O)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 80 °C
Reaction time: 14 h
Yield: 46.6 %

Procedure:
A mixture of 5-bromo-2,4-dichloropyrimidine (1.25 g, 5.5 mmol) and 1-(2-aminophenyl)ethanone (675 mg, 5.0 mmol) with sodium bicarbonate (1.26 g, 15.0 mmol) in 4:1 EtOH/THF (7.5 mL) was stirred at 80° C. for 14 hours. The reaction was cooled to room temperature and the resulting mixture was filtered, washing the solid with cold EtOH. The collected solid was stirred in hot water, filtered, and the resulting solid washed with cold EtOH. The solid was then dried under vacuum to give 1-{2-[(5-bromo-2-chloropyrimidin-4-yl)amino]phenyl}ethanone (761 mg, 47%) as a yellow solid. 1H NMR (DMSO-d6): δ 11.91 (s, 1H), 8.60-8.64 (m, 2H), 8.15 (d, 1 H), 7.74 (t, 1 H), 7.31 (t, 1 H), 2.72 (s, 3 H). MS m/z 326 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]4[N:31]([C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=4)[N:32]=3)[CH2:23][CH2:22]2)[CH:16]=1)=[O:13].[I-].[Na+]>C1COCC1.CC(N(C)C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]5[N:31]([C:33]([C:36]([F:39])([F:37])[F:38])=[N:34][N:35]=5)[N:32]=4)[CH2:23][CH2:22]3)[CH:16]=2)=[O:13])[CH2:4][CH2:3]1
Reactant: O=C(CCCCl)Nc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCCC(=O)Nc2cccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2)CC1
Temperature: 60 °C
Yield: 47.8 %

Procedure:
1-Methylpiperazine (152 μl, 1.37 mmol) was added to 4-chloro-N-[3-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]butanamide (160 mg, 0.343 mmol) and sodium iodide (10 mg, 0.069 mmol) in a mixture of THF (2 mL) and DMA (0.5 mL). The resulting solution was heated at 60° C. for 16 hours, then cooled and evaporated to give the crude product, which was purified by flash chromatography on silica, eluting with a gradient of 0-10% 2M ammonia in methanol in DCM. The solvents were evaporated, then the resulting gum triturated with ether and the precipitate filtered and dried to give 4-(4-methylpiperazin-1-yl)-N-[3-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]butanamide (87 mg, 48%) as a solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][CH2:18][CH2:19][OH:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[OH-].[Na+]>ClCCl.O>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:20][CH2:19][CH2:18][CH2:17][C:9]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: BrCCCCCBr
Reactant: OCCCc1nc2ccccc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: BrCCCCCOCCCc1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20.9 %

Procedure:
A mixture of 1-(phenylmethyl)-2-benzimidazolepropanol (3.0 g), 1,5-dibromopentane (7.77 g), TAB (0.5 g) and 40% sodium hydroxide (5 ml) in dichloromethane (10 ml) was stirred at room temperature for 6 h under nitrogen. The mixture was diluted with water (100 ml) and extracted with dichloromethane (2×30 ml). The dried extracts were evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether (10:0→0:10) gave the title compound as a colourless oil (0.98 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[C:5]#[N:6].CO>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: N#Cc1cc(N)cc(Cl)c1
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cc(N)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 3-amino-5-chlorobenzonitrile in THF at RT was added slowly borane methyl sulfide complex (2.5 eq.). The resulting reaction mixture was stirred at RT for 1 h and heated at reflux for 2 hrs. The reaction mixture was cooled to −30° C. and MeOH was added slowly to quench the reaction. Solvent was evaporated in vacuo after the reaction mixture was stirred at RT for 30 min. to give 3-amino-5-chlorobenzylamine, which was used without purification. LCMS (Method A) RT 0.16 min., MH30 157.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C@H:15]([C:20]([NH:22][C@H:23]([CH:36]=[O:37])[CH2:24][C:25](=[N:31][NH:32][C:33]([NH2:35])=[O:34])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:14][C@H:15]([C:20]([NH:22][C@H:23]([CH:36]=[O:37])[CH2:24][C:25](=[N:31][NH:32][C:33]([NH2:35])=[O:34])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
1-Methylindole-2-carboxylic acid (70 mg, 0.4 mmol) and 3(S)-(Leucinyl)amino-4-oxobutanoic acid, t-butyl ester semicarbazone (131 mg, 0.4 mmol) were dissolved in methylene chloride (2 mL) and both DMAP (49 mg, 0.40 mmol) and EDAC (107 mg, 0.56 mmol) were added to the solution under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and an additional 3 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution. The ethyl acetate solution was washed successively with 5% KHSO4 solution, saturated with sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated in vacuo to give a crude solid. Trituration of the solid with ether afforded the title product as a white powder (156 mg, 80%). TLC: (methanol/methylene chloride: 5/95, silica gel): Rf=0.42; 1H NMR (CDCl3+CD3OD): δ 8.18 (s, 1H), 7.66-7.11 (m, 6H), 6.97 (s, 1H), 6.32 (d, J=7.7, 1H), 4.95-4.88 (m, 1H), 4.70-4.62 (m, 1H), 4.03 (s, 3H), 2.82-2.56 (m, 2H), 1.87-1.58 (m, 3H), 1.38 (9H), 1.00 (t, J-6.3, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Product: COc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenol: ESMS m/e: 520.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](OCC)=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: O=CCc1cccc(Br)c1

Procedure:
Important starting materials for the synthesis of the preferred compounds of the invention are 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F), 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G), and the isomeric bromo compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H). Compound G can be obtained as described in J. Med. Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). The isomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can be obtained, starting with ethyl (4-bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction Scheme 1 for Compound G. 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al. Tetrahedron, 41, 1509-1516 (1985).
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([O:15][CH2:16][C:17](OCC)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[CH2:8]([O:15][CH:16]([CH:17]=[O:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC=O
Reactant: CCOC(=O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(C=O)OCc1ccccc1

Procedure:
To a suspension of sodium hydride (3.3 g, 60% in paraffin oil, 82.5 mmol) in dry ether (100 mL) and dry ethyl formate (5.55 g, 75 mmol) was added ethyl (benzyloxy)acetate (14.57 g, 75 mmol) dropwise with stirring. The resulting mixture solution was then refluxed for 2 h and concentrated to give crude ethyl 2-(benzyloxy)-3-oxopropanoate which was used in the subsequent step without further purification.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:34](O)(=[O:36])[CH3:35]>>[C:34]([N:17]1[CH2:18][CH2:19][C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[C@H:15]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:16]1)(=[O:36])[CH3:35]
Reactant: CC(=O)O
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: CC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and acetic acid (6.9 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:15](=O)[C@@H:14]3[C@H:17]([OH:20])[CH2:18][CH2:19][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:15][C@@H:14]3[C@H:17]([OH:20])[CH2:18][CH2:19][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(N2C[C@@H]3[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 4 h
Yield: 6.2 %

Procedure:
To a solution of compound 23G (150 mg, 0.5 mmol) in anhydrous THF (12 mL) cooled to −78° C. was added dropwise 1.0 M LiEt3BH solution in THF (0.5 mL, 0.5 mmol). After addition, the reaction was stirred at −78° C. for 4 h, then quenched by addition of saturated aqueous Na2CO3 (5 mL). The reaction was warmed to 0° C., 30% H2O2 (˜0.5 mL) was added, and the reaction was stirred at 0° C. for 30 min, then extracted with CH2Cl2 (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure overnight. The residue (˜120 mg) was dissolved in anhydrous CH2Cl2, and to the resulting solution cooled to −78° C. was added dropwise triethylsilane (0.5 mL, 3.1 mmol), followed by boron trifluoride diethyl etherate (0.5 mL, 3.9 mmol). The reaction mixture was stirred at −78° C. for 2 h, then additional triethylsilane (0.3 mL, 1.88 mmol) and boron trifluoride diethyl etherate (0.3 mL, 2.35 mmol) were added, and the reaction was stirred at 0° C. overnight. The reaction was then quenched with saturated aqueous Na2CO3 (10 mL), then extracted with CH2Cl2 (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give a crude product (˜100 mg). The crude product was purified using preparative HPLC to give 30 mg, which was further purified using chiral preparative HPLC to afford the title compound (9 mg). HPLC: 98% at 4.39 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min UV detection at 220 nm). Chiral HPLC: retention time=10.59 min (99%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in hexane for 30 min at 1 mL/min; MS (ES) m/z 292 [M+1]+.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:23])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Yield: 96.5 %

Procedure:
Dissolve dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10)-trien-17-one (7.0 g) in methanol (300 ml) and treat with sodium borohydride (3.0 g). After spontaneous reflux ceases, acidify the reaction mixture with 50% acetic acid (20 ml). Work up by the usual procedures to obtain dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10) -trien-17β-ol (6.8 g), m.p. 158°-160°; infrared absorption peaks (potassium bromide) at 3.05 μ, 6.45 μ.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C:55]1[CH:56]=[C:57]([C:61]2[N:70]=[C:69]([NH:71][C:72]3[CH:73]=[C:74]4[C:78](=[CH:79][CH:80]=3)[N:77]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[N:76]=[CH:75]4)[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[N:62]=2)[CH:58]=[CH:59][CH:60]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([NH:54][C:55]2[CH:56]=[C:57]([C:61]3[N:70]=[C:69]([NH:71][C:72]4[CH:73]=[C:74]5[C:78](=[CH:79][CH:80]=4)[N:77]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[N:76]=[CH:75]5)[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]=3)[CH:58]=[CH:59][CH:60]=2)=[O:11])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: CN1CCN(CC(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CC(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(4-methylpiperazin-1-yl)acetic acid (34 mg, 0.22 mmol), PyBOP® (11 mg, 0.22 mmol), DIEA (300 μL, 1.72 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 1 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-(2-(4-methylpiperazin-1-yl)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)=O)(C)(C)C.C(OC([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1B1OB(C2CC3C(=CC=CC=3)N2C(OC(C)(C)C)=O)O1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[C:34]1[NH:33][C:41]2[C:36]([CH:35]=1)=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(OCc3ccccc3)ccc21
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1B1OB(c2cc3ccccc3n2C(=O)OC(C)(C)C)O1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(COc2ccc3[nH]nc(-c4cc5ccccc5[nH]4)c3c2)cc1
Yield: 80.9 %

Procedure:
Stage Ib: A suspension of 3.23 g of 5-benzyloxy-3-iodoindazole-1-carboxylic acid tert-butyl ester, 7.31 g of 2-[4-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-2-yl)-1,3,2,4-dioxadiboretan-2-yl]indole-1-carboxylic acid tert-butyl ester, 2.07 g of palladium tetrakistriphenylphosphine and 11 ml of a saturated aqueous sodium bicarbonate solution is heated at reflux for approximately two hours and then at ambient temperature overnight. The reaction medium is filtered through paper, and the filtrate is then diluted with 150 ml of ethyl acetate. The organic phase is washed with 200 ml of distilled water. The aqueous phase is extracted with 2×150 ml of ethyl acetate. The organic phases are combined and washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The solvent is evaporated off under vacuum in a rotary evaporator. The resulting crude product is purified by flash chromatography on silica 70-200 μm, eluent: cyclohexane/ethyl acetate gradient 95:5 to 70:30 to obtain 1.97 g of 5-benzyloxy-3-(1H-indol-2-yl)-1H-indazole.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNc1ccc(Cl)cn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccc(Cl)cn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-[(2-aminoethyl)amino]-5-chloropyridine hydrochloride and DBU in DME. ES-MS m/e (%): 356 (M+H+, 100).