Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][CH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]1[NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH2:32][C@@H:33]4[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]4[NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1CN
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Reaction time: 1.3 h

Procedure:
A mixture of 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 15a, (0.42 g, 0.90 mmol) and tert-butyl trans-2-(aminomethyl)cyclohexylcarbamate (0.24 g, 1.06 mmol) were heated in THF (10 mL) to 70° C. After 1.3 hours, the mixture was concentrated in vacuo. Flash chromatography (SiO2, O-60% EA/Hex, gradient elution) provided the desired intermediate, tert-butyl trans-2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexylcarbamate, 14e, as a racemic mixture of trans isomers, which was taken into the next reaction without further purification (0.52 g, 92% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]3[CH2:22][CH2:23][S:24][CH2:25][CH:26]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].[C:28]([C:30]1[N:31]=[C:32]([C:43]([O-])=[O:44])[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=1)#[N:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:43]([C:32]3[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=[C:30]([C:28]#[N:29])[N:31]=3)=[O:44])=[C:16]([C:21]3[CH2:26][CH2:25][S:24][CH2:23][CH:22]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCSCC3)c2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCSCC3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a mixture of 4-[4-amino-3-(3,6-dihydro-2H-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 45 mg, 0.12 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 3, step (d), 44 mg, 0.144 mmol) and PyBroP (67 mg, 0.144 mmol) in 2 mL of DMF was added DIEA (42 μL, 0.24 mmol). The resulting mixture was stirred at RT for 4 h under Ar. Treated with 30 mL of EtOAc, the mixture was washed with H2O (3×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-2% EtOAc/DCM) gave 64 mg (85%) of the title compound as a light yellow oil. 1H-NMR (CDCl3; 400 MHz): δ 9.51 (s, 1H), 8.21 (d, 1H, J=8.5 Hz), 7.78 (s, 1H), 7.16 (dd, 1H, J=8.5, 2.1 Hz), 7.02 (d, 1H, J=2.1 Hz), 6.00 (m, 1H), 5.92 (s, 2H), 4.25 (br s, 2H), 3.66 (t, 2H, J=8.2), 3.42 (m, 2H), 2.93 (dd, 2H, J=5.7, 5.7 Hz), 2.79 (m, 2H), 2.63 (dddd, 1H, J=12.3, 12.3, 3.3, 3.3 Hz), 2.49-2.56 (m, 2H), 1.82 (d, 2H, J=12.8 Hz), 1.56-1.66 (m, 2H), 1.49 (s, 9H), 0.97 (t, 2H, J=8.2 Hz), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7]3[NH:12][C:11]4[N:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]=32)[CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][CH2:30][N:12]2[C:7]3[CH2:6][CH2:5][N:4]4[CH:9]([C:8]=3[C:10]3[CH:16]=[CH:15][CH:14]=[N:13][C:11]2=3)[CH2:1][CH2:2][CH2:3]4)=[CH:37][CH:36]=1
Reactant: c1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4cccnc42)C2CCCN2CC3)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (120 mg, 0.565 mmol) in DMF (1 mL) was added a suspension of NaH (68.0 mg, 1.69 mmol) in DMF (1 mL). After stirring for 5 min at rt, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (492 mg, 1.69 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h at RT. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography (MeOH-DCM) to yield 7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:49])[CH2:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[CH:39]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:49])[CH2:35][O:36][C:37](=[O:48])[C:38]4[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[CH:39]=4)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: COc1cc(OC)cc(C(=O)OC[C@H](C)NC(C)C)c1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COC(=O)c3cc(OC)cc(OC)c3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridin-6-yl)benzoic acid and 3,5-dimethoxy-benzoic acid (S)2-isopropylamino-propyl ester as described for example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[NH2:17][CH2:18][CH2:19][CH:20]([NH:29][C:30](=[O:46])[CH2:31][NH:32][S:33]([C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)(=[O:35])=[O:34])[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>>[CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:44]=[CH:45][C:36]=1[S:33]([NH:32][CH2:31][C:30]([NH:29][CH:20]([C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:19][CH2:18][NH:17][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:46])(=[O:35])=[O:34]
Reactant: NCCC(NC(=O)CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Agent: Cl
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CCNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Yield: 17 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with N-[3-amino-1-(piperidinocarbonyl)propyl]-2-(2-naphthalenesulphonamido)-acetamide hydrochloride salt to give 2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-propyl}acetamide in 17% yield;
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]([CH3:20])[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>C(O)(=O)C.C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([N:18]([CH3:20])[CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(N(C)C)n2)CCC3c2ccc(Cl)cc2)ccc1-n1cnc(Cl)c1
Temperature: 75 °C

Procedure:
2-Chloro-7-(4-chlorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (98 mg, 0.318 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (71.1 mg, 0.318 mmol) in acetic acid (1.000 mL) and THF (1 mL). The reaction mixture was heated at 75° C. overnight. Partial conversion to the desired product was observed. The reaction was further heated at 120° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N4,N4-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (17.2 mg, 0.028 mmol, 8.70% yield). LC-MS (M+H)+=495.1. 1H NMR (500 MHz, CDCl3) δ ppm 11.80 (1H, s), 7.61-7.72 (1H, m), 7.34-7.42 (2H, m), 7.27-7.33 (2H, m), 7.21 (2H, d, J=8.5 Hz), 7.16 (1H, d, J=9.2 Hz), 7.06 (1H, d, J=1.5 Hz), 4.30-4.41 (1H, m), 3.82 (6H, s), 3.48 (1H, br. s.), 3.31-3.39 (2H, m), 3.18-3.27 (1H, m), 2.58-2.80 (2H, m), 2.14-2.29 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:8]([O:12][CH3:13])[C:9]([OH:11])=O)[CH:7]=1.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:8]([O:12][CH3:13])[C:9]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:16]#[N:15])=[CH:18][CH:19]=2)=[O:11])[CH:7]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1cc(Br)ccc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cc(Br)ccc1F

Procedure:
(RS)-(5-Bromo-2-fluoro-phenyl)-methoxy-acetic acid was reacted with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-(5-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Colorless solid. MS 377.2 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10][CH:9]1[C:17]([O-:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH:24][C:17]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)[O-]
Reactant: Nc1c(F)cccc1F
Agent: [Li+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (589 mg, 2.18 mmol, Eq: 1.00) and 2,6-difluoroaniline (480 mg, 0.4 mL, 3.72 mmol, Eq: 1.71) in pyridine (7 mL) (ice-bath) was added dropwise phosphoryl trichloride (660 mg, 0.4 mL, 4.3 mmol, Eq: 1.97). The cooling bath was removed and the resulting yellow/orange suspension was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with water (20 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine (1×5 mL). The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 100% EtOAc in DCM/hexanes (1:1)). After the combined fractions were concentrated, the off-white solid was treated with 5% MeOH/ether (˜10 mL) to give tert-butyl 2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a white solid (532 mg).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C[Al](C)C.O.O1CCO[CH2:34][CH2:33]1>CCCCCC.[Cu]Br>[C:1]([O:4][CH:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][C@@H:13]([CH2:33][CH3:34])[C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Reactant: C1COCCO1
Agent: [Cu]Br
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: O
Product: CC[C@@H]1C[C@H]2[C@@H]3CC=C4CC(OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(C)=O
Temperature: 22 °C
Reaction time: 3 h

Procedure:
3.56 g (10 mmol) of 3-acetoxy-pregna-5,16-dien-20-one is dissolved in 20 ml of dioxane at 20° C. and mixed with 143.3 g (1 mmol) of copper(I) bromide. 11 ml (11 mmol) of a 1 molar solution of trimethyl aluminum in hexane is added to the reaction at room temperature under nitrogen atmosphere and, after completion of the addition, stirred for 3 hours more at 22° C. For hydrolysis of the reaction solution, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate is filtered off with dioxane and washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 1.72 g of 3-acetoxy-16α-ethyl-pregn-5-en-20-one (45% of theory) of a melting point of 114.9° C. is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][N:33]=2)[CH2:28][CH2:27]1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([C:35]4[CH:34]=[N:33][C:32]([N:29]5[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]5)=[N:37][CH:36]=4)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CN1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cnc(N4CCN(C)CC4)nc3)ccc1-2

Procedure:
Following Example 267, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxyethyl)-isopropylamide and 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine to give 270. MS: (ESI+)=509.2
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([CH2:10][NH:11][CH3:12])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[O:15]=[C:16]1[CH2:21][O:20][C:19]2[CH:22]=[C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)[CH:24]=[N:25][C:18]=2[NH:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([CH2:10][N:11]([CH3:12])[C:28](=[O:30])/[CH:27]=[CH:26]/[C:23]3[CH:24]=[N:25][C:18]4[NH:17][C:16](=[O:15])[CH2:21][O:20][C:19]=4[CH:22]=3)=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Reactant: CNCc1sc2ccc(F)cc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
To a solution of (5-fluoro-3-methylbenzo[b]thiophen-2-yl)-N-methyl methanamine (200 mg, 0.96 mmol) in DMF (5 mL) were added in sequential order (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (185 mg, 0.87 mmol), 1-hydroxybenzotriazole (133 mg, 0.96 mmol), diisopropylethylamine (454 uL, 2.61 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (192 mg, 0.96 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product was extracted with ethyl acetate (3×10 mL), dried with sodium sulfate, filtered and concentrated. The crude product was purified using preparative HPLC to give the title compound (45 mg, 13%): 1H NMR (400 MHz, DMSO-d6) δ 11.42 (bs, 1H), 8.19 (s, 1H), 7.89-7.87 (m, 2H), 7.55-7.51 (m, 2H), 7.22-7.18 (m, 2H), 5.12-4.87 (2s, 2H, rotamers), 4.68 (s, 2H), 3.54 (s, 3H), 2.39 (s, 3H). MS (ESI) m/e 412 (C21H18FN3O3S+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1.[ClH:23]>>[ClH:23].[NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([OH:12])[CH2:10][CH2:11]1
Reactant: CCOC(=O)c1cc(Br)c(N)c(CN[C@H]2CC[C@H](O)CC2)c1
Agent: Cl
Product: Nc1c(Br)cc(C(=O)O)cc1CN[C@H]1CC[C@H](O)CC1

Procedure:
2-Amino-3-bromo-5-carboxy-N-(trans-4'-hydroxy-cyclohexyl)-benzylamine hydrochloride, m.p. 279° C (decomp.) was prepared from 2-amino-3-bromo-5-carbethoxy-N-(trans-4'-hydroxy-cyclohexyl)-benzylamine and 6 N hydrochloric acid analogous to Example 272.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:21]3[CH2:20][CH2:19][CH:18]([NH2:22])[CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37].Cl>C(Cl)Cl>[F:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:21]3[CH2:20][CH2:19][CH:18]([NH:22][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([O:23][C:24]([F:27])([F:25])[F:26])[CH:14]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1
Yield: 52.1 %

Procedure:
Dissolve 9-(6-fluoro-pyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-ylamine (Preparation 47) (580 mg, 1.53 mmol) and triethylamine (201 mg, 277 μL, 1.99 mmol) in CH2Cl2 (20 ML). Slowly add isobutyryl chloride (212 mg, 208 μL, 1.99 mmol) and stir at room temperature for 18 h. Dilute the reaction with dilute HCl (10 mL), then load the reaction onto a Varian ChemElut CE1020 solid-phase extraction cartridge (Varian part number 12198008). Elute, collect, and concentrate 125 mL CH2Cl2 to give the crude product (794 mg) as a brown oil. Purify the crude product on silica gel (40 g), eluting with 35-65% EtOAc/hexanes to afford 358 mg (52%) of the title compound as a yellow foam. MS (ES): m/z 450 (M+1), 448 (M−1); HPLC (Method B): Rt=8.21 min (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[CH3:24].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:12][C:10]2[O:11][C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:31])=[CH:33][CH:34]=1)[CH3:24]
Reactant: COc1ccc(-c2ccccc2)c2oc(N)nc12
Reactant: COCCN(C)Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(-c4ccccc4)c3o2)cc1

Procedure:
From 4-methoxy-7-phenyl-benzooxazol-2-yl-amine with 4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzoyl chloride, triethylamine and N,N-dimethyl-4-aminopyridine in THF. ES-MS m/e (%): 446 (M+H+, 100).
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[N:14][CH:15]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:12]=[CH:11][C:10]([N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][S:1]4(=[O:8])=[O:7])=[CH:15][N:14]=3)=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 71.9 %

Procedure:
Using [1,2]thiazinane 1,1-dioxide (94 mg) and (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (260 mg) described in Preparation Example 134 and by the reaction and treatment in the same manner as in Example 1, the title compound (214 mg) was obtained.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([S:17]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18])[CH:9]=[CH:8]2.O.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39]([OH:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(O)CCC.C1C=CC=CC=1>[N:1]#[N:2].[C:33]1([CH3:43])[CH:34]=[CH:35][C:36]([S:39]([OH:42])(=[O:40])=[O:41])=[CH:37][CH:38]=1.[CH2:38]([O:30][C:29](=[O:31])[C@H:21]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH2:28])[NH:20][S:17]([C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:11]=1)(=[O:18])=[O:19])[CH2:33][CH2:34][CH3:35]
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: CCCCO
Solvent: c1ccccc1
Solvent: O
Product: CCCCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Yield: 92 %

Procedure:
A mixture of 1.0 g of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine and 1.0 g of p-toluenesulfonic acid monohydrate in 5 ml of butyl alcohol and 30 ml of benzene was refluxed for 5 hours, while removing the water formed during the reaction. The reaction mixture was concentrated under reduced pressure, and to the residue was added ethyl ether to yield a crystalline substance which was collected by filtration, washed several times with ethyl ether to afford N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine butyl ester p-toluenesulfonate: yield 92%, m.p. 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](N)=[C:16]2[CH2:19][S:20][CH2:21][C:15]2=[N:14]1.N(OCCC(C)C)=O>CN(C=O)C>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[CH:17]=[C:16]2[CH2:19][S:20][CH2:21][C:15]2=[N:14]1
Reactant: Nc1c2c(nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl)CSC2
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Cl)c(-n2cc3c(n2)CSC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of 2-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4,6-dihydrothieno-[3,4-c]pyrazole-3-ylamine (200 mg, 0.56 mmol) in DMF (5 mL) is warmed up to 65° C. and isoamyl nitrite (0.3 mL) was added dropwise and the reaction mixture stirred for 1 h at the same temperature. After cooling to room temperature, the mixture was extracted with ethyl ether (50 mL) and washed with brine (4×25 mL). After drying the organic phase (MgSO4), volatile materials were removed under reduced pressure, and the residue was subjected to flash chromatography on silica, (10% ethyl acetate:hexanes). The product was recrystallized (hexane) and obtained in 76% yield. 1H NMR (CDCl3) δ 7.72 (s, 2H), 4.01 and 4.09 (m, 2H each); MS (M+) 339.