Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]2)[O:4]C1C.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1)([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccccc1N1CCC2(CC1)OCC(C)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccccc1N1CCC(=O)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 44 (5.3 g, 18 mmol) in methanolic HCl (200 mL) was heated in an oil bath (50° C., 1 h). The resulting mixture was cooled, diluted with water (50 mL), and stirred at room temperature (30 min). The solvent volume was reduced in vacuo and neutralized with sodium carbonate. The aqueous layer was extracted with three portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6 mm, 10% EtOH-90% CHCl3) afforded the title compound (45).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[B:24]1[O:28]C(C)(C)[C:26](C)(C)[O:25]1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[N:8]=1)=O.[BH4-].[Na+].Cl>CO>[OH:28][B:24]1[C:23]2[CH:22]=[CH:21][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[N:8]=3)=[CH:4][C:3]=2[CH2:26][O:25]1
Reactant: COCCN(C)c1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCN(C)c1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Reaction time: 8 h
Yield: 2.6 %

Procedure:
To a clear solution of 6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile (7) (15 g, 343 mmol) in MeOH (anhydrous, 300 mL) was slowly added NaBH4 (7.83 g, 206 mmol). The reaction was stirred at room temperature 4 hours, before the addition of HCl solution (1 M, 200 mL). The stirring was kept at room temperature overnight. Then the solution was slowly evaporated in vacuo. Purification was accomplished by reverse phase Biotage with 10%-100% MeOH/H2O gradient to afford 3 g (26% yield) of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.13-7.09 (m, 2H), 6.23 (d, J=8.2 Hz, 1H), 5.08 (s, 2H), 4.78 (s, 1H), 3.56 (t, J=5.7 Hz, 2H), 3.36 (t, J=5.7 Hz, 2H), 3.27 (s, 3H), 3.23 (s, 3H); ES-MS: m/z 340 (M+H)+; HPLC: 99.38% (220 nm), 98.71% (MaxPlot).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH:5]=[C:6]([CH2:15][C:16](OCC)=[O:17])[CH:7]=[CH:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:4]3[CH:5]=[C:6]([CH2:15][CH2:16][OH:17])[CH:7]=[CH:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCOC(=O)Cc1ccc2sc3ncnc(Cl)c3c2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCCc1ccc2sc3ncnc(Cl)c3c2c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate (850 mg, 2.77 mmol, 1.00 equiv) in freshly distilled THF (15 mL) cooled down to −78° C. in a liquid N2/ethanol bath under nitrogen. Then DIBAL-H (4.42 mL, 2.00 equiv) was added dropwise with stirring at −78° C. in 10 min and the resulting solution was stirred for 2 h at this temperature. The resulting solution was allowed to react, with stirring, for an additional 1 h at room temperature and quenched with water, extracted with 3×100 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (4/1) to give the 2-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-6-yl)ethanol (500 mg, 68%) as a yellow solid. LCMS (ES, m/z): 265 and 267 (M+H+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9](C(O)=O)=[N:10][C:4]2=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[N:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 319.5 %

Procedure:
A 100 ml RBF equipped with magnetic stir bar and N2 inlet was charged with 356 mg (2.06 mmol, 1 eq) 2-quinaldic acid in 10 ml dry DMF. The solution was cooled to 0° C. and 415 mg (3.07 mmol, 1.5 eq) HOBt was added followed by 415 mg EDC (2.16 mmol, 1.05 eq). The reaction was stirred 2 hours at 0° C. when 1.1 g (2.06 mmol, 1 eq) of free asparagine amine in 10 ml dry DMF was added. The reaction was stirred at 0° C. for 2 hours then room temperature overnight. The reaction was poured into sat. bicarb and extracted with 2×65 mL ethyl acetate. The combined organics were washed with 5% aq. citric acid, brine, dried and concentrated to 1.4 g crude foam. Purification by flash chromatography on silica gel (100% ethyl acetate) yielded 850 mg (61%) of quinoline adduct.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[C:31]([CH:32]=[O:33])=[C:30]([N:34]3[CH2:46][CH2:45][N:37]4[C:38]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[C:36]4[C:35]3=[O:47])[N:29]=[CH:28][CH:27]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:33][CH2:32][C:31]1[C:30]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[N:29][CH:28]=[CH:27][C:26]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:20][CH2:21]3)=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To the solution of 103c (500 mg, 0.8 mmol) in methanol (50 mL) was added sodium borohydride (91 mg, 2.4 mmol) at 0° C. and stirred for another 30 minutes. Then the reaction mixture was quenched with water (3 mL) and concentrated. The residue was purified with reverse-phase prep-HPLC to afford 103 (224 mg, 45%). LCMS: [M+H]+ 637. 1H NMR (500 MHz, DMSO) δ 8.61 (d, J=3.0, 1H), 8.48 (d, J=6.0, 1H), 7.92 (d, J=3.5, 1H), 7.81 (d, J=3.0, 1H), 7.78 (s, 1H), 7.38 (d, J=6.0, 1H), 7.24-7.27 (m, 1H), 6.88 (s, 1H), 6.81 (d, J=11.5, 1H), 5.01-5.04, (m, 1H), 4.60-4.71 (m, 5H), 4.32-4.49 (m, 2H), 3.83-4.15 (m, 3H), 3.70 (s, 3H), 3.53-3.59 (m, 1H), 3.13-3.16 (m, 4H), 2.55-2.61 (m, 4H), 2.49-2.52 (m, 4H), 1.78-1.90 (m, 4H)
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[CH3:5][C:6]([CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][CH2:9]1)=[O:7]>>[CH3:14][C:12]1([CH3:15])[CH2:11][CH2:10][CH2:9][CH:8]([C:6]([OH:7])([CH2:3][CH:2]=[CH2:1])[CH3:5])[CH2:13]1
Reactant: C=CCCl
Reactant: CC(=O)C1CCCC(C)(C)C1
Product: C=CCC(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with allyl chloride replacing bromoethane, and herbac replacing dehydroherbac.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[C:5](O)=[O:6])=O.[BH4-].[Na+].II.CO>O1CCCC1>[CH3:1][NH:3][C@H:4]([CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][OH:6]
Reactant: O=CN[C@H](Cc1cccs1)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN[C@@H](CO)Cc1cccs1
Temperature: 9.5 °C
Yield: 105.8 %

Procedure:
A solution of (2R)-2-(formylamino)-3-(2-thienyl)propionic acid (3.58 g, 18.0 mmol) in tetrahydrofuran (50 ml) was added dropwise to a suspension of sodium borohydride in tetrahydrofuran (50 ml), which was cooled to 7-12° C. (inside temperature). After the addition was finished, a solution of iodine (4.57 g, 18.0 mmol) in tetrahydrofuran (100 ml) was added dropwise. The reaction mixture was heated to reflux for 16 h. It was cooled to 0° C. Methanol (200 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in a freshly prepared 20% aqueous sodium hydroxide solution (200 ml). The aqueous phase was extracted with tert-butyl methyl ether (4×150 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo to give 3.26 g of crude (2R)-2-methylamino-3-(2-thienyl)propan-1-ol, which was used for the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])(C)[C:9]#N.CCO.C([O-])([O-])=O.[K+].[K+].OO.CC#[N:26]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:26])([CH3:12])[CH3:9]
Reactant: CC(C)(C#N)c1ccccc1Cl
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(N)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2-(2-Chlorophenyl)-2-methylpropanenitrile (5.0 g, 0.028 mol) along with 50 mL of EtOH was added into a 250 mL round-bottomed flask. To this was added 50 mL of saturated aqueous K2CO3. This mixture was cooled to 0° C. then 85 mL of 30% aqueous H2O2 was slowly added. The reaction mixture was allowed to warm to room temperature, and then it was stirred at that temperature for 12 h. The mixture was extracted with CH2Cl2 (3×150 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a viscous oil. To this oil was added 40 mL of CH3CN, 40 mL H2O, and 13.2 g (0.031 mol) of PhI(O2CCF3)2. This mixture was stirred at r.t. for 12 h, diluted with 300 mL of H2O, and then stirred for an additional 4 h at room temperature. The aqueous phase was extracted using MTBE (1×200 mL) follow by diethyl ether (2×100 mL). The aqueous layer was basified with 1N NaOH (pH=13) and then extracted with CH2Cl2 (3×100 mL). The organic extracts were dried and concentrated in vacuo to give the desired product as a colorless oil that was used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C)C=O.O>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:19]1[C:20]([CH3:21])=[C:6]2[C:7]([CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=32)=[CH:18]1
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1cc2c(c1C)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In one portion, 2.0 g (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added to an ice-cooled solution of 0.8 g (7.1 mmol) of potassium t-butoxide in 30 ml of dry dimethylformamide. After stirring at 0° C. for 15 minutes, 0.65 ml (7.7 mmol) of methyl bromoacetate was added, and the resulting solution was stirred for 5 minutes. The mixture was diluted with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to an oily residue. Purification of the residue by column chromatography (silica gel, 40 g; eluent, 5% ether in methylene chloride) gave after crystallization from a mixture of ether and petroleum ether 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid methyl ester as off-white prisms, mp 174°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 18, Methanesulfonic acid 5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and Diethanolamine were converted to yield 2-[{5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-(2-hydroxy-ethyl)-amino]-ethanol, MS: 415 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:36])=[C:23]([C:26]4[O:27][C:28]([CH:31]5OCC[O:32]5)=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37]>C1COCC1>[ClH:37].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:36])=[C:23]([C:26]4[O:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C2OCCO2)o1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cc2F)o1
Reaction time: 1.5 h
Yield: 61 %

Procedure:
Prepared according to Procedure C from a stirred solution of (4-benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine (0.51 grams, 1.1 mmol) in 20 ml of THF was added 5 ml of 1N HCl. After stirring for 90 minutes, the resultant suspension was filtered and washed with diethyl ether (200 ml) to yield, after drying under vacuum, a yellow solid (0.32 grams, 61% yield). δ1H NMR (400 MHz, DMSO-d6) 11.52 (s, 1H), 9.70 (s, 1H), 9.25 (d, 1H), 8.76 (s, 1H), 7.76 (m, 2H), 7.55 (d, 2H), 7.45 (d, 2H), 7.33 (m, 4H), 7.11 (d, 2H), 5.14 (s, 2H). ESI-MS m/z 440 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:10]2)[CH3:2].[O:21]=[C:22]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C@@H:38]([C:52](O)=[O:53])[CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[C:43]([NH2:50])=[C:42]([Cl:51])[CH:41]=3)=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]2[CH:55]=[CH:56][CH:57]=[CH:58][C:24]=2[NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:21]=[C:22]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C@H:38]([CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[C:43]([NH2:50])=[C:42]([Cl:51])[CH:41]=3)[C:52]([N:17]3[CH2:16][CH2:15][N:14]([CH:9]4[CH2:10][CH:11]5[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH:7]([CH2:13][CH2:12]5)[CH2:8]4)[CH2:19][CH2:18]3)=[O:53])=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]2[CH:55]=[CH:56][CH:57]=[CH:58][C:24]=2[NH:23]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)CN1C2CCC1CC(N1CCNCC1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1C2CCC1CC(N1CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
113 mg (0.40 mmol) ethyl(3-piperazin-1-yl-8-aza-bicyclo[3.2.1]oct-8-yl)-acetate (Example A12d) were added to a mixture of 200 mg (0.45 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 128 mg (0.40 mmol) TBTU and 56 μL (0.40 mmol) triethylamine in 2 mL DMF and the reaction mixture was stirred for 2 h at RT. This was purified by HPLC without any further working up; the fractions containing the product were combined and evaporated down i. vac.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][O:32][CH2:31]4)[CH2:26][C@@H:25]3[CH3:34])=[CH:20][N:19]=2)[C:3]1=[O:35].Cl[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([N:43]2[C:55](=[O:56])[C:54]3[S:53][C:52]4[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=4[C:46]=3[CH:45]=[N:44]2)[C:38]=1[CH:57]=[O:58].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:1][N:2]1[C:3](=[O:35])[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][O:32][CH2:31]4)[CH2:26][C@@H:25]3[CH3:34])=[CH:20][N:19]=2)=[CH:5][C:6]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([N:43]3[C:55](=[O:56])[C:54]4[S:53][C:52]5[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=5[C:46]=4[CH:45]=[N:44]3)[C:38]=2[CH:57]=[O:58])=[CH:7]1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 191j (168 mg, 0.35 mmol), 4-chloro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 124a (121 mg, 0.35 mmol), K3PO4 (148 mg, 0.70 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (13 mg, 0.0175 mmol), sodium acetate trihydrate (95 mg, 0.70 mmol), water (6 drops), and acetonitrile (10 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. under N2 protection for 1 h. Analysis of reaction mixture by LCMS showed completed conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (30 mL) and water (30 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 191k (118 mg, 51%) as yellow solid. MS-ESI: [M+H]+ 665
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH2:8])=[NH:7].[Cl:18][C:19]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:20]=1[CH:21]=[C:22]([C:25]#[N:26])[C:23]#[N:24]>>[NH2:26][CH2:25][C:22]1[C:23]([NH2:24])=[N:7][C:6]([C:5]2[CH:4]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=2)=[N:8][C:21]=1[C:20]1[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:19]=1[Cl:18]
Reactant: N=C(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=481.2 (M+H+), was prepared from 3,5-bis-trifluoromethyl-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 79 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 79%). 1H NMR (300 MHz, CDCl3): δ 2.42-2.49 (m, 3H), 3.12-3.19 (m, 4H), 3.79 (s, 3H), 4.11-4.13 (m, 4H), 6.97-7.12 (m, 5H), 7.26-7.33 (m, 1H), 7.48-7.63 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:31]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([F:31])=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a cooled (-15° C.) solution of t-butoxycarbonyltryptophan (1.2 g, 4 mmol) and pyridine (0.35 ml, 4 mmol) in methylene chloride (10 ml) is dropped cyanuric fluoride (0.72 ml, 36 mmol) and the mixture is stirred at -15° C. for 1 hour. The reaction mixture is diluted with methylene chloride and ice, and filtered on Celite. The filtrate is diluted with ice water and extracted with methylene chloride. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give t-butoxycarbonyltryptophan fluoride.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[CH2:10][CH2:11][C:12]([NH:14][C:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH3:17])[CH3:16])=[O:13]>C1COCC1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])([CH3:17])[CH3:16])=[CH:23][CH:22]=1
Reactant: Cc1ncc[nH]1
Reactant: CC(C)(NC(=O)CCCl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nccn1CCC(=O)NC(C)(C)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52c, a mixture of 2-methylimidazole (1.3 g) and sodium hydride (0.63 g, 60% dispersion) in THF (35 ml) was treated with a mixture of 3-chloro-N-[1-(4-chlorophenyl)-1-methylethyl]propionamide (4.0 g) in THF (15 ml) to give N-[1-(4-chlorophenyl)-1-methylethyl]-3-(2-methylimidazol-1-yl)propionamide as an oil which was used directly in part (b) below.
Reaction SMILES: Cl.[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=O>>[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][N:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:18][CH2:19]1
Reactant: O=C(C1CCc2ccccc2O1)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: c1ccc(CN2CCN(CC3CCc4ccccc4O3)CC2)cc1

Procedure:
By carrying out the preparation in the same way as in Example 1, but starting with the hydrochloride of 1-[(chroman-2-yl)carbonyl]-4-benzylpiperazine obtained in Stage A, the title compound is obtained.