Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:20][C:21]([F:25])([F:24])[CH2:22][OH:23])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26](=O)[CH3:27].[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:30].[Na+]>CO.C(O)(=O)C.O>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:8]([CH2:20][C:21]([F:24])([F:25])[CH2:22][OH:23])[C:7]2[C:2]([N:1]([CH2:26][CH3:27])[CH2:29][CH3:30])=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Nc1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(F)(F)CO)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(F)(F)CO)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{7-amino-2-[(2,4-dichlorophenyl)amino]-1H-benzimidazol-1-yl}-2,2-difluoropropan-1-ol (51.0 mg, 0.132 mmol) in methanol (1.3 mL) and acetic acid (26 μL) was added acetaldehyde (49 μL, 0.790 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (176.2 mg, 0.790 mmol) at 0° C. After 1 hr, the mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as an amorphous (49.8 mg, 0.112 mmol, 85%).
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O.C(O)(=O)C>C(O)C.O>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=Cc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1cccs1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium hydroxide (2.0 g) was added to a suspension of estrone (1.352 g, 5.0 mmol) and thiophene-2-carboxaldehyde (561 mg, 5.0 mmol) in ethanol (40 mL). The resulting dark brown solution was stirred for 4 hours at room temperature, then acetic acid (5 mL) and water (5 ml) were added, the product started to precipitate after a few minutes and was filtered off, washed with water (20 mL), ethanol (10 mL) and diethyl ether (10 mL) and dried under high vacuum. Yield: 1.614 g (89%) yellow solid. 1H-NMR (CDCl3, 400 MHz) δ: 0.98 (s, 3H, —CH3), 1.44-1.78 (m, 5H), 2.02-2.14 (m, 2H), 2.26-2.46 (m, 3H), 2.84-3.02 (m, 3H), 4.98 (s, 1H, —OH), 6.62 (d, J=2.7 Hz, 1H), 6.67 (dd, J=8.6, 2.7 Hz, 1H), 7.14 (dd, J=5.1, 3.5 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.35 (d, J=3.5 Hz, 1H), 7.53 (d, J=5.1 Hz, 1H), 7.67 (s, 1H). LRMS (FAB+): 365.2 (100, [M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH3:19])[S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])=[O:7].[N:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]2[C:37]3[C:32](=[CH:33][C:34]([CH:38]=O)=[CH:35][CH:36]=3)[N:31](COCC[Si](C)(C)C)[N:30]=2)=[CH:23][CH:22]=1>>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH3:19])[S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:38][C:34]1[CH:33]=[C:32]2[C:37]([C:29](/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=3)=[N:30][NH:31]2)=[CH:36][CH:35]=1)(=[O:8])=[O:7]
Reactant: CN(C)CCN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Product: CN(C)CCN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2

Procedure:
The title compound was synthesized according to the method described in Example A57 from N-(2-(dimethylamino)ethyl)-N-methyl-2-oxoindoline-5-sulfonamide and (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (25 mg, 0.065 mmol) with a modified purification procedure. The product was extracted into EtOAc, and washed with NaHCO3(sat) (2×), brine (2×) and the organic layer dried over MgSO4. After removal of solvent the resulting yellow solid was titurated with Et2O/hexanes to give after drying 1.5 mg, 4.1% yield of a yellow solid which was a 77:23 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, CD3OD) δ 9.01, 8.03 (s, 1H), 8.55-8.45 (m, 2H), 8.30-8.05 (m, 3H), 7.96-7.76 (m, 2H), 7.75-7.65 (m, 3H), 7.58-7.51 (m, 1H), 7.10, 7.07 (d, J=8.6 Hz, 1H), 3.05-2.99 (m, 2H), 2.90, 2.72 (m, 2H), 2.80, 2.63 (s, 3H), 2.57, 2.34 (s, 6H); MS ESI 529.2 [M+H]+, calcd for [C28H28N6O3S+H]+ 529.20.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2Br)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(OCC)(=O)C.[CH3:33][N:34](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[C:33]#[N:34])[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc3ccncc3cc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc3ccncc3cc2C#N)CC1

Procedure:
Under argon atmosphere 35 mg (0.3 mmol) of Zn(CN)2 and 17 mg (0.05 eq) of Pd(PPh3)4 were added to a solution of 122 mg (0.3 mmol) of 4-(7-bromo-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (13) in DMF. The reaction was heated for 5 minutes to 150° C. in a microwave reactor (CEM Discovery). After cooling to room temperature water and ethyl acetate were added. The mixture was filtered through Celite, washed with ethyl acetate and concentrated. The crude product was purified by preparative HPLC to yield 77 mg of compound 16.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][NH:27][C@H:28]([C:32]([O:34][CH3:35])=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH3:26][N:27]([C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1)=[O:18])[C@H:28]([C:32]([O:34][CH3:35])=[O:33])[CH:29]([CH3:31])[CH3:30]
Reactant: CN[C@H](C(=O)OC)C(C)C
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C(C)C)N(C)C(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
4′-Nitro-1,1′-biphenyl-4-carboxylic acid (0.50 g, 2.0 mmol) was dissolved in methylene chloride (25 mL), and then oxalyl chloride (0.27 mL, 3.1 mmol) was added, followed by one drop of N,N-dimethylformamide. The resulting mixture was heated at 50° C. for 1 h, concentrated under reduced pressure, and further dried under vacuum for 30 min. The residue was dissolved in methylene chloride (20 mL) and added dropwise to an ice-cold mixture of methyl N-methyl-L-valinate hydrochloride (0.48 g, 2.6 mmol), methylene chloride (50 mL), and triethylamine (1.44 mL, 10.2 mmol). The resulting solution was stirred on ice for 1 h and then at rt overnight. The mixture was diluted with methylene chloride and washed with 1N aqueous HCl solution and brine. The organic layer was separated and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage® system, 3:1 hexanes/EtOAc) to afford methyl N-methyl-N-[(4′-nitro-1,1′-biphenyl-4-yl)carbonyl]-L-valinate (0.70 g, 92%). 1H NMR (400 MHz, CDCl3) δ 0.85 (dd, 3H), 1.06 (dd, 3H), 2.31 (m, 1H), 3.02 (d, 3H), 3.77 (d, 3H), 3.94 (d, 0.5H), 4.98 (d, 0.5H), 7.52 (m, 2H), 7.64 (m, 2H), 7.72 (t, 2H), 8.27 (d, 2H); LC-MS m/z 371.2 (MH+), retention time 3.27 minutes.
Reaction SMILES: Cl.[OH:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:4]1=[O:31].[Cl:32]CCl.CO.[C:37](O)(=[O:39])[CH3:38].Cl>C(OC(=O)C)(=O)C.CCOCC>[ClH:32].[C:37]([O:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:4]1=[O:31])(=[O:39])[CH3:38]
Reactant: COc1ccc([C@H]2Cc3cc(C(F)(F)F)ccc3N(CCN(C)C)C(=O)[C@H]2O)cc1
Reactant: ClCCl
Reactant: CC(=O)O
Agent: Cl
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COc1ccc([C@H]2Cc3cc(C(F)(F)F)ccc3N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1

Procedure:
A stirred suspension of (cis)-3-(hydroxy)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride (1.50 g; 3.27 mmol) in 50 ml of acetic anhydride was heated in an oil bath at 110°-117° C. (solution obtained) for 2.5 hours (under argon). TLC (8:1:1 dichloromethane-methanol-acetic acid) showed the reaction to be complete. The acetic anhydride was removed on a rotary evaporator at 0.2 mm to give a solid. The latter was rubbed under ethyl acetate, 1 ml of saturated hydrogen chloride in ether (to pH 2) was added and the evaporation repeated. The colorless material was rubbed under ether, cooled overnight, filtered, washed in ether, and dried in vacuo; yield 1.43 g; melting point 230°-232° C. (dec.); s. 227° C. TLC: Rf =0.41 (8:1:1 dichloromethane-methanol-acetic acid).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:26])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:9]2)[C:5]([F:27])=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1)#[N:29].C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O.C(=O)(O)[O-].[Na+]>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[N:7]=[C:6]([C@:8]3([CH3:26])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[N:9]3)[C:5]([F:27])=[CH:4][CH:3]=2)=[O:37])=[N:34][CH:35]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(NC(=O)c3ccc(C#N)cn3)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 25 °C
Yield: 146.2 %

Procedure:
To a solution of tert-butyl ((4S,6S)-4-(6-amino-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7k, 0.101 mg, 0.13 mmol) in EtOAc (4 mL) was added 5-cyano-2-pyridinecarboxylic acid (0.042 mg, 0.28 mmol, Aldrich), di-isopropylethylamine (0.09 mL, 0.51 mmol), and 1-propanephosphonic acid cyclic anhydride (0.18 mL, 0.28 mmol, 50 wt. % solution in ethyl acetate, Alfa-Aesar). The reaction mixture was stirred at room temperature for 2 hs. The reaction was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc (10 mL). The organic layer was washed sequentially with water and brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the crude material was purified via silica gel flash chromatography (gradient 0-30% EtOAc in hexanes) to afford the title compound as a white solid (0.097 g, 0.19 mmol, 72% yield). MS m/z=523.2 [M+H]+. Calculated for C23H22F4N6O4: 522.4
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][C:7](=[CH2:9])[CH2:6][N:5]1[C:10](=[O:29])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Br:25])=[CH:13][C:12]=1[N+:26]([O-:28])=[O:27].CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1.C(Cl)Cl.C1(C)C=CC=CC=1.CO>[Br:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([C:10]([N:5]2[CH2:6][C:7](=[CH2:9])[CH2:8][C@H:4]2[CH:3]=[O:2])=[O:29])=[C:12]([N+:26]([O-:28])=[O:27])[CH:13]=1
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)c2cc(OC)c(OCCCCCBr)cc2[N+](=O)[O-])C1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: C=C1C[C@@H](C=O)N(C(=O)c2cc(OC)c(OCCCCCBr)cc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
To a vigorously stirred solution of 1-[4-(5-bromopentyloxy)-5-methoxy-2-nitro-benzoyl]-4-methylene-L-proline methyl ester 18 (61 mg, 0.12 mmol) in anhydrous toluene —CH2Cl2 (3:1, 2.5 mL) was added dropwise solution of DIBAL-H (188 μL of a 1M solution in toluene) at −78° C. under argon atmosphere. After the mixture was stirred for an additional 45 min, excess reagent was decomposed by addition of three drops of methanol followed by 5% HCl (2 mL). The resulting mixture was allowed to warm to 0° C. Layers were separated and the aqueous layer was further extracted with CH2Cl2 (3×2 mL). Combined organic layers were washed with brine, and dried (MgSO4) and concentrated. Purification of the residue by flash chromatography (silica gel, 1:1 hexanes/EtOAc) yielded (S)-1-[4-(5-bromopentyloxy)-5-methoxy-2-nitro-benzoyl]-4-methylene-2-pyrrolidinecarboxaldehyde 19 as light yellow oil (44 mg, 80%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.FC(F)(F)C([N:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=O.[OH-].[Na+]>ClCCl.O1CCOCC1.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:21]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][CH2:13][CH2:14]3)(=[O:22])=[O:23])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc3c(c2)CCN3)CC1
Reaction time: 0.75 h

Procedure:
N-Methylpiperazine (4.41 mL, 39.7 mmol, 2.00 equiv) was added to a solution of 1-(trifluoroacetyl)indoline-5-sulfonyl chloride (1-6, 6.23 g, 19.9 mmol, 1 equiv) in dichloromethane (50 mL) at 23° C., and the resulting mixture was stirred for 45 minutes. The brown-colored reaction mixture was concentrated and the residue dried in vacuo to give a tan solid. A suspension of the solid in a mixture of 1,4-dioxane (130 mL) and methanol (35 mL) was then treated with aqueous 1N NaOH solution (81.6 mL, 81.6 mmol, 3.00 equiv) and stirred for 1 hour. The mixture was concentrated, and the resulting solids were suspended in diethyl ether (175 mL), filtered, and dried in vacuo. The resulting solid was then partitioned between saturated sodium chloride solution (200 mL) and ethyl acetate (4×100 mL). The organic layer was dried over sodium sulfate and concentrated to provide the 5-[(4-methylpiperazin-1-yl)sulfonyl]indoline (1-7) as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ 7.26 (s, 1H), 7.25 (d, 1H, J=7.8 Hz), 6.52 (d, 1H, 8.1 Hz), 6.48 (s, 1H), 3.55 (t, 2H, J=8.8 Hz), 3.00 (t, 2H, J=8.54 Hz), 2.79 (br s,4H), 2.34 (br s, 4H), 2.13 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[NH:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C1(C)C=CC=CC=1.CCCCCC>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:18]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:12][CH:13]=1
Reactant: N=C(Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C

Procedure:
To a solution of crude 2,4-dichloro-N-(4-chlorophenyl)benzenecarboximidamide (10.3 g, 34.6 mmol) in toluene (100 mL), ethyl bromopyruvate (4.3 mL, 34.6 mmol) and Na2CO3 (7.3 g, 41.6 mmol) were added. The resulting solution was heated at reflux for 3 h. The reaction mixture was cooled to rt. The solid was filtered off and the solvent was evaporated. The residue was purified by flash chromatography over silica gel (40% ethyl acetate in hexane) to give the product (7.5 g, 52% overall yield from 4-chroloaniline) as a light yellow solid: LC-MS m/z 395 (MH+), retention time 3.91 min (method 1); mp 143-144° C.; Rf=0.63 (50% EtOAc in hexane). 1H NMR (300 MHz, CDCl3) δ 1.39-1.43 (3H, t, J=7.2 Hz), 4.39-4.46 (2H, q, J=6.9 Hz), 7.04-7.08 (2H, m), 7.25-7.50 (5H, m), 7.89 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:8][C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:4]=1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: Cc1[nH]nc(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1c(Cl)c(N)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.18-7.22 (d, 1H), 6.78-6.84 (d, 2H), 4.8 (s, 2H), 4.4 (s, 2H), 3.72-3.82 (m, 4H), 3.08-3.18 (m, 4H), 2.14 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:7]=1.[CH3:25][N:26]([CH3:33])[CH2:27][CH:28]=[CH:29][C:30](Cl)=[O:31]>>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH:3]=[CH:4][C:5]=3[CH3:24])[CH:14]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CN(C)CC=CC(=O)Cl
Reactant: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Product: Cc1ccc(NC(=O)/C=C/CN(C)C)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1

Procedure:
N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl) pyrimidine-4,6-diamine (Int-F) and 4-dimethylamino-2-butenoyl chloride were combined in a manner similar to that described in Scheme 4a to give (E)-N-[3-(6-{3-chloro-4-fluorophenyl}amino-pyrimidin-4-ylamino)-4-methylphenyl]-4-(dimethylamino)but-2-enamide (I-54). MS (m/z): 455/457 (M+1, 100/39%). 1H NMR (DMSO-d6) δ 11.02 (bs, 1H), 10.66 (bs, 1H), 9.92 (bs, 1H), 9.39 (bs, 1H), 7.92-7.94 (m, 1H), 7.75 (bs, 1H), 7.27-7.56 (m, 4H), 6.80 (m, 1H), 6.54 (d, 1H), 5.89 (bs, 1H), 3.92 (bs, 2H), 2.75 (bs, 6H), 2.17 (bs, 3H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][N:15](C)[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2.COC1C=C2C(=CC=1OC)[C@@H](CN)C2.C1COCC1>O1CCOCC1>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C@@H:8]([CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]1[CH2:21][CH2:22][C:23]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:24]=3[CH2:25][CH2:26]1)=[O:19])[CH2:7]2
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Agent: COc1cc2c(cc1OC)[C@@H](CN)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CCN(C(=O)CCNC[C@H]1Cc3cc(OC)c(OC)cc31)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the racemic [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}amine and of the THF by dioxane.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:13][C@@H:14]([NH2:30])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:31][C:32]1([C:38]([Cl:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl.O>[CH:7]1([CH2:13][C@@H:14]([NH:30][C:38]([C:32]2([CH3:31])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:39])[CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:20][CH2:21]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[ClH:40]
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: COc1ccccc1C1CCN(C[C@H](N)CC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1C1CCN(C[C@@H](CC2CCCCC2)NC(=O)C2(C)CCCCC2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 0.076 g of potassium carbonate (0.54 mmol) in 1 ml. of water was added a solution of 0.18 g of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl}-amine (0.54 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0° C. and 0.085 g of 1-methyl-cyclohexanecarbonyl chloride (0.54 mmol) was added. The reaction was allowed to stir overnight at 0° C., and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases separated. The aqueous phase was extracted with three additional portions of dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride.0.75 hydrate salt of the title compound with isopropanolic HCl to yield 0.35 g (55%) as a white solid; mp=208-210° C.; MS (+) ESI m/z=455 (M+H)+.
Reaction SMILES: [H-].[Na+].CO[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][CH:6]=1.[Cl:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]3[O:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH:26]([CH3:38])[C:24]3=2)[NH:19][CH:18]=1.O.CN([CH:43]=[O:44])C>>[Cl:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]3[O:30][CH2:29][CH2:28][NH:27][CH:26]([CH3:38])[C:24]3=2)[N:19]([S:12]([C:8]2[CH:9]=[C:10]([CH3:11])[CH:5]=[CH:6][C:7]=2[O:44][CH3:43])(=[O:13])=[O:14])[CH:18]=1
Reactant: CN(C)C=O
Reactant: CC1c2c(ccc3[nH]cc(Cl)c23)OCCN1C(=O)OC(C)(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C)cc1S(=O)(=O)n1cc(Cl)c2c3c(ccc21)OCCNC3C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 18 mg, 0.74 mmol) was added to a solution of 6-methoxy-m-toluensulfonyl chloride (98.3 mg, 0.445 mmol) and tert-butyl 10-chloro-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 43, 50.0 mg, 0.148 mmol) in DMF (2 mL) at room temperature. The mixture was stirred for 15 minutes before water (5 mL) was added and the aqueous layer was extracted with DCM. Most of the organic solvents were evaporated and the residue was dissolved in DCM (1 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes. Solvents were evaporated and the crude product was purified by preparative HPLC (Xterra C18, 10 mM NH4HCO3 (pH 10) —CH3CN) to give the title compound as a white solid (16.8 mg). MS m/z 421 [M+H]+.