Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[CH:13][CH:14]=2)[C:9]1=[O:21]>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:18][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[CH:17][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:21])=[CH:14][CH:13]=1
Reactant: Cc1ccncc1-n1ccc2ccc([N+](=O)[O-])cc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1-n1ccc2ccc(N)cc2c1=O
Reaction time: 3.3 h
Yield: 79.9 %

Procedure:
10% Pd—C (20 mg) was added to a solution of 2-(4-methyl-pyridin-3-yl)-7-nitro-2H-isoquinolin-1-one (I-24b: 140 mg, 0.4982 mmol) in methanol (8 mL) under nitrogen atmosphere. The resulting mixture was hydrogenated in a Parr hydrogenator at room temperature for 3.30 hours. The reaction was monitored by TLC (5% methanol in CHCl3). The reaction mixture was filtered; the filtrate was concentrated and dried to afford 100 mg of the product (79.9% yield).
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21][O:22][CH2:23]Cl>CN(C)C=O>[CH3:21][O:22][CH2:23][N:9]1[C:8]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:7]=2[S:6][C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:10]1=2
Reactant: COC(=O)c1ccc2c(c1)Nc1nccnc1S2
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1c2cc(C(=O)OC)ccc2Sc2nccnc21
Temperature: -5 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
415 g of methyl 10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate was suspended in 2.5 l of N,N-dimethylformamide in a nitrogen atmosphere. Then 66 g of sodium hydride (oily: 60% or more) was added in portions thereto while maintaining the mixture at −10 to 0° C. Then the resulting mixture was stirred for 1 hour. Next, 110 g of chloromethyl methyl ether was dropped thereinto while maintaining the mixture at a temperature not exceeding 5° C. After the completion of the reaction, the reaction mixture was poured into ice, extracted with methylene chloride twice, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, diisopropyl ether was added to the residues and the crystals thus precipitated were taken up by filtration to thereby give 335 g of the title compound as yellow crystals.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH2:37]([O:41][C:42]1[CH:78]=[CH:77][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:72])[CH3:71])[C:66]([O:68]C)=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[C:51]([C:73]([F:76])([F:75])[F:74])[CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]>>[CH2:37]([O:41][C:42]1[CH:78]=[CH:77][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:71])[CH3:72])[C:66]([OH:68])=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[C:51]([C:73]([F:75])([F:76])[F:74])[CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)c(C(F)(F)F)c2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)c(C(F)(F)F)c2)cc1
Yield: 82 %

Procedure:
The compound of example 432 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 431.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[N+:27]([O-])=O)[CH2:14][C:15]([O:17]C)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[NH:27][C:15](=[O:17])[CH2:14]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1[N+](=O)[O-])C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC(=O)Nc3cc(Cl)ccc3C2)C1

Procedure:
To a solution of 3-[(4-Chloro-2-nitro-benzyl)-methoxycarbonylmethyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g, 2.4 mmol) in ethyl acetate (20 mL) was added 10% Pd/C. Hydrogenolysis of the reaction solution at rt under atmospheric pressure provided the desired product after 1.5 h. The reaction mixture was filtered through a pad of celite and concentrated. The crude product (662 mg, 1.7 mmol) was dissolved in DMF (5 mL) and to it was added 60% NaH (100 mg, 2.5 mmol). The resultant solution was stirred at rt overnight. The reaction was quenched with water and extracted with ethyl ether. The organic extract was dried over MgSO4, filtered and concentrated to get the crude product. Purification on SiO2 provided the desired product. LCMS (retention time=1.89, ES+; 310)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[NH3:27]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH2:27])[C:11]=2[CH:10]=[CH:9]1
Reactant: N
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Product: Cc1ccccc1-n1ccc2c(N)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-methylphenyl)-4-chloro-6-trifluoromethoxypyrrolo[3,2-c]quinoline(377 mg, 1.0 mmol) was dissolved in aqueous ammonia(10 ml), then reacted at the same condition of Step 3 in the Example 6 to obtain 29 mg of desired compound as solid in 8% of yield.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]#[N:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]#[N:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C#N)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C#N)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 54.4 %

Procedure:
Prepared in 54.4% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-cyano-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.15-8.08 (m, 2H), 7.57 (t, J=7.7 Hz, 1H), 7.40 (d, J=7.3 Hz, 1H), 7.22 (d, J=9.5 Hz, 1H), 7.16 (d, J=5.5 Hz, 2H), 5.86 (br. s., 1H), 4.61 (br. s., 1H), 3.81 (t, J=12.3 Hz, 1H), 3.61 (t, J=11.4 Hz, 1H), 3.43 (br. s., 3H), 3.23-3.15 (m, 1H), 2.73 (br. s., 1H), 2.63 (s, 3H), 1.96-1.60 (m, 9H), 1.53 (br. s., 1H), 1.20 (s, 3H), 1.17 (s, 9H), 1.06 (d, J=5.9 Hz, 3H); LCMS (ESI, M+1): 669.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[CH:18]=[CH:17][C:13]2[O:14][CH2:15][O:16][C:12]=2[CH:11]=1>>[CH2:15]1[O:14][C:13]2[CH:17]=[CH:18][C:10]([CH2:9][N:1]3[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]3)=[CH:11][C:12]=2[O:16]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: O=C1CCNCC1
Product: O=C1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
1-(3,4-Methylenedioxy)benzyl-4-piperidone is prepared from 4-piperidone and 5-chloromethyl-1,3-benzodioxole essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:13]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)(=[O:10])=[O:9].[H-].[Na+].IC.[CH2:35](Cl)Cl>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH3:35])[C:12]1[C:13]([C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)(=[O:9])=[O:10]
Reactant: ClCCl
Reactant: O=C(c1nn(-c2ccccc2)cc1NS(=O)(=O)c1ccccc1Br)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cn(-c2ccccc2)nc1C(=O)N1CCOCC1)S(=O)(=O)c1ccccc1Br
Reaction time: 12 h
Yield: 97 %

Procedure:
To a solution of 2-bromo-N-[3-(morpholin-4-ylcarbonyl)-1-phenyl-1H-pyrazol-4-yl]benzenesulfonamide (30 mg; 0.06 mmol; 1.00 eq.) in THF (6 mL) is added sodium hydride (3 mg; 0.07 mmol; 1.20 eq.) and the reaction is stirred for 10 min before the addition of iodomethane (4 μL; 0.07 mmol; 1.10 eq.). After 12 h, DCM is added to the reaction mixture, ished with water (×2) and dried the organic phase over MgSO4 give 30 mg (97%) of the title compound as a white solid. 1H NMR (DMSO) δ 8.64 (s, 1H), 7.93-7.86 (m, 2H), 7.80-7.73 (m, 2H), 7.62-7.47 (m, 4H), 7.41-7.32 (m, 1H), 3.65-3.51 (m, 6H), 3.48-3.42 (m, 2H), 3.35 (s, 3H). HPLC (max plot) 89.7%; Rt 3.98 min. MS (ESI+): 507.2.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([N:9]3[CH2:12][CH:11]([OH:13])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1.C(O)C>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:15]=[CH:14][C:5]3[N:6]=[C:7]([N:9]4[CH2:12][CH:11]([OH:13])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[CH:19]=[N:18]1
Reactant: OC1CN(c2nc3ccc(Br)cc3s2)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCO
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc3nc(N4CC(O)C4)sc3c2)cn1
Temperature: 150 °C

Procedure:
A mixture of 1-(6-bromobenzo[d]thiazol-2-yl)azetidin-3-ol (Reference Example 1, 1.426 g, 5.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS #761446-44-0, 1.248 g, 6.0 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.140 g, 0.20 mmol), and (2-biphenyl)dicyclohexylphosphine (0.070 g, 0.20 mmol) in 1:1 dioxane/ethanol (12 mL) was treated with deoxygenated 1 M aqueous Na2CO3 (6.0 mL). The reaction mixture was then heated under microwave irradiation at 150° C. for 10 minutes. The reaction mixture was then diluted with dichloromethane (30 mL) and filtered through a pad of diatomaceous earth that was subsequently rinsed with 9:1 dichloromethane/methanol. The filtrate was concentrated under reduced pressure and the residue was treated with acetonitrile (20 mL) to provide a slurry that was filtered. The filter cake was treated with 4:1 methanol/water (5 mL) and the resulting slurry was filtered. The filter cake was rinsed with 4:1 methanol/water (3 mL), then dried under vacuum to provide 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-ol. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.82-3.91 (m, 2H), 3.85 (s, 3H), 4.31 (t, J=8 Hz, 2H), 4.62-4.72 (m, 1H), 5.86-5.91 (m, 1H), 7.43 (d, J=8 Hz, 1H), 7.48 (dd, J=1, 8 Hz, 1H), 7.82 (d, J=1 Hz, 1H), 7.96 (d, J=1 Hz, 1H), 8.07 (s, 1H); MS (DCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13](C(OC(C)(C)C)=O)[CH3:14])=[CH:9][C:8]=1[Cl:22])[CH3:2].COC(=O)COC1C=CC(N(C(OC(C)(C)C)=O)C)=CC=1Cl.C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[Cl:22])[CH3:2]
Reactant: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1Cl
Agent: COC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(NC)cc1Cl

Procedure:
Analogously, to example 1.4, crude [4-(tert-butoxycarbonyl-methyl-amino)-2-chloro-phenoxy]-acetic acid ethyl ester containing [4-(tert-butoxycarbonyl-methyl-amino)-2-chloro-phenoxy]-acetic acid methyl ester was TFA deprotected to give (2-chloro-4-methylamino-phenoxy)-acetic acid ethyl ester containing (2-chloro-4-methylamino-phenoxy)-acetic acid methyl ester, MS: 244 (MH+, 1Cl) and 230 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=3)(=[O:26])=[O:25])[CH:22]=2)[NH:17][CH:16]=1>C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:35]([O:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][S:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:14][CH2:13][NH:12][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:26])=[O:25])=[CH:29][CH:30]=1)[CH3:36]
Reactant: CCOc1ccc(NS(=O)(=O)c2ccc3[nH]cc(CCN)c3c2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOc1ccc(NS(=O)(=O)c2ccc3[nH]cc(CCNC(=O)OCc4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (1.55 ml) was added portionwise to a stirred solution of the product of Example 4 (4.3 g) in a mixture of ethyl acetate (100 ml) and sodium carbonate (2 N, 100 ml) and the resulting mixture stirred at room temperature for 1 h. The aqueous layer was extracted with ethyl acetate (100 ml), the organic extracts combined, washed with hydrochloric acid (1 N, 100 ml), sodium carbonate (2 N, 100 ml) dried (MgSO4) and evaporated in vacuo to give an oil. The oil was purified by flash chromatography eluted with chloroform:methanol (19:1) to give the title compound as a foam which collapsed to a gum (2.4 g) T.l.c. Silica, Chloroform-methanol (19:1) det. u.v.+CeIVRf 0.34
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:35](=[O:37])[CH3:36])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CCC4)c23)ccc1OCc1ccccn1
Reactant: CC(=O)Cl
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CCC1
Yield: 42 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(cyclobutylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 42% yield; NMR spectrum (DMSO-d6) 1.50-1.65 (m, 2H), 2.01 s, 3H), 2.12-2.21 (m, 4H), 3.94 (t, 2H), 4.28-4.38 (m, 3H), 5.31 (s, 2H), 7.19 (d, 1H), 7.26 (d, 1H), 7.32-7.40 (m, 2H), 7.57-7.62 (m, 2H), 7.69-7.76 (m, 1H), 7.86-7.91 (m, 1H), 7.97 (s, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.90 (s, 1H); Mass spectrum MH+ 518.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)[CH:15]=1)=[O:12])C(=O)[O-])(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[NH2:5][CH2:9][CH:10]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)[CH:15]=1)=[O:12]
Reactant: Cn1nccc1-c1cccc(NC(=O)C(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1-c1cccc(NC(=O)C(CN)Cc2ccccc2)c1
Reaction time: 1 h
Yield: 52 %

Procedure:
1,1-dimethylethyl[3-{[3-(1-methyl-1H-pyrazol-5-yl)phenyl]amino}-3-oxo-2-(phenylmethyl)propyl]carbamate (170 mg, 0.39 mmol) was dissolved in DCM (10 mL) and treated with TFA (1 mL). After 1 h, the solution was concentrated and purified using reverse-phase HPLC (C18 column: H2O/CH3CN, 40-10%) affording the bis-TFA salt of the title compound (115 mg, 52%) as a white solid. LC-MS (ES) m/z=335 (M+H)+, 1H NMR (d4-MeOD, 400 MHz) δ 7.76 (br s, 1H), 7.43 (br s, 1 h), 7.35-7.23 (m, 9H), 4.55 (m, 1H), 3.72 (s, 3H), 3.23 (dd, J=3.5, 13.1 Hz, 1H), 3.13 (dd, J=10.4, 13.1 Hz, 1H), and 3.03-2.95 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]#[N:38]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:36][C:37]#[N:38])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(O)cn2)CC1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(OCC#N)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.5 %

Procedure:
To a stirred solution of 4-[tert-butoxycarbonyl-(5-hydroxy-pyridin-2-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.79 g, 2.0 mmol, 1.0 equiv) in acetonitrile (20 mL) was added potassium carbonate (0.84 g, 6.0 mmol, 3.0 equiv), followed by bromoacetonitrile (0.21 mL, 0.37 g, 3.0 mmol, 1.5 equiv). After stirring at rt for 16 h, the reaction mixture was poured into ice water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.93 g (100%) of the title compound as light brown oil. MS (ISP): 433.3 [M+H]+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([C@H:14]1[C:23]3[C:18](=[C:19]([F:28])[CH:20]=[C:21]([C:24]([O:26]C)=[O:25])[CH:22]=3)[O:17][CH2:16][CH2:15]1)[CH2:9]2>C(O)C.O>[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([C@H:14]1[C:23]3[C:18](=[C:19]([F:28])[CH:20]=[C:21]([C:24]([OH:26])=[O:25])[CH:22]=3)[O:17][CH2:16][CH2:15]1)[CH2:9]2
Reactant: COC(=O)c1cc(F)c2c(c1)[C@H](N1Cc3cccc(Cl)c3C1=O)CCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(F)c2c(c1)[C@H](N1Cc3cccc(Cl)c3C1=O)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
KOH (1 mol/l aq) (2 eq) was added to a suspension of (R)-methyl 4-(7-chloro-1-oxoisoindolin-2-yl)-8-fluorchromane-6-carboxylate (D-05) (0.8 mmol, 1 eq) in a mixture of ethanol (4.6 ml) and water (1.6 ml). The reaction mixture was stirred overnight at RT. Ethanol was removed in vacuo and the residue was taken up in diethyl ether and water. The phases were separated and the aqueous phase was adjusted to pH 3 with 1N HCl. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate:cyclohexane 1:1). Yield: 62% B. Amine Structural Units Overview: Amine Structural Units
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28]1[N:29]=[C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[S:31][CH:32]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[S:31][CH:32]=[C:28]([C:22]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=4[F:20])[N:29]=3)[CH2:34][CH2:35]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)c(F)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccc(F)cc4F)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (255 mg, 0.782 mmol), 1-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 190 mg (58.2%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].[Li]CCCC.CON(C)[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:19]>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([F:9])=[C:2]([CH:7]=1)[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:19]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Fc1ccc(Cl)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Cl)ccc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A solution of 2-bromo-4-chloro-1-fluorobenzene (175 μL, 1.377 mmol) in THF (4.59 mL) at 78° C. was treated with n-BuLi (2.6 M, 741 μL, 1.928 mmol) and the reaction mixture was stirred for 30 min. To this was added tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 mg, 0.918 mmol) in one portion. The cooling bath was removed and the resulting reaction mixture was allowed to warm to rt and stirred for 1.5 h. Purification by automated flash silica gel chromatography using 10% EtOAc in hexanes afforded tert-butyl 4-(5-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (287.9 mg, 92%) as a yellow oil. ESI-MS m/z [M+Na]+ 364.20.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[CH:8]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:10][C:5]2=[CH:4][CH:3]=1.Br[CH2:18][C:19](=O)[CH3:20].C(=O)([O-])O.[Na+]>C(O)C>[CH3:20][C:19]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]3[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:6]=3[N:7]2[CH:18]=1
Reactant: CC(=O)CBr
Reactant: CC(=O)NCCC1CCc2ccc(N)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NCCC1CCc2ccc3nc(C)cn3c21
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
A suspension of N-[2-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)ethyl]acetamide (17.6 mg, 0.0803 mmol), bromoacetone (16.5 mg, 0.120 mmol) and sodium hydrogen carbonate (10.1 mg, 0.12 mmol) in ethanol (1 mL) was heated under reflux for 4 hr. The solvent was evaporated under reduced pressure, and N,N-dimethylformamide (1 mL) was added. The mixture was irradiated with 150 W microwave and stirred at 160° C. for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (methanol/ethyl acetate=17/83 and NH; methanol/ethyl acetate=5/95) to give the title compound (2.0 mg, yield 10%).