Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(Cl)=CC=CC=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[Na+].[I-].[Cl:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[N:38]1CCCN(CCCCOC2C=C3C(CCC(=O)N3)=CC=2)CC1.CCN(C(C)C)C(C)C>CC#N>[Cl:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[N:38]1[CH2:9][CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: Clc1cccc(C2CCN(CCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(N2CCCN(CCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
A mixture of intermediate 44 (43.7 mg, 0.17 mmol) and NaI (51.3 mg, 0.34 mmol) in CH3CN (3 mL) was heated to reflux for 30 min and then cooled to rt. To this mixture was added intermediate 2 (57.9 mg, 0.21 mmol), followed then by DIEA (0.066 mL, 0.38 mmol). The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by ISCO to give 6-(3-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)propoxy)-1H-indazole (compound 46) (43.6 mg, 61%). 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J=0.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.15-7.07 (m, 2H), 7.00 (dd, J=7.4, 2.3 Hz, 1H), 6.88 (s, 1H), 6.80 (dd, J=8.8, 2.1 Hz, 1H), 4.09 (t, J=6.1 Hz, 2H), 3.43-3.37 (m, 2H), 3.29 (t, J=6.1 Hz, 2H), 3.14-3.05 (m, 4H), 3.00-2.92 (m, 2H), 2.22-2.10 (m, 4H). HPLC: 99%, RT 4.201 min. MS (ESI) m/z 419.10 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[N-]=C=O.ClC1C=CC=CC=1C(O[CH:37]1[CH2:40][N:39]([C:41](NC(C)(C)C)=[O:42])[CH2:38]1)C1C=CC=CC=1Cl>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([O:13][CH:14]1[CH2:17][N:16]([C:41]([NH:39][CH2:38][CH:37]=[CH2:40])=[O:42])[CH2:15]1)[C:4]1[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=1[Cl:2]
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Agent: Cl
Agent: [N-]=C=O
Product: C=CCNC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH2:27][CH2:28][CH2:29][CH:30]([OH:34])[C:31]([OH:33])=[O:32].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([NH:27][CH2:28][CH2:29][CH:30]([OH:34])[C:31]([OH:33])=[O:32])=[N:3][CH:4]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: NCCC(O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(NCCC(O)C(=O)O)c(-c2ccn[nH]2)c1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 20 mg, 0.05 mmol), 4-amino-2-hydroxybutanoic acid (23.4 mg, 0.200 mmol), K3PO4 (106 mg, 0.501 mmol) and NMP (0.4 mL) were added to a MW vial, which was sealed, flushed with argon and stirred at 170° C. for 1 h. The RM was filtered and the residue washed with NMP. The combined organic phases were acidified with TFA, diluted with water and MeCN, filtered and purified by preparative HPLC (Condition 11—gradient to 50% B in 7 min). The MeCN was evaporated off under reduced pressure to give an aqueous solution which was left for 2 days at 4° C. The resulting precipitate was filtered, washed with water and dried to afford the title compound as a white solid. UPLC-MS (Condition 8) tR=0.93 min, m/z=482.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.73-1.91 (m, 1H) 1.99-2.17 (m, 1H) 3.58-3.82 (m, 2H) 4.07 (s, 1H) 5.22-5.50 (m, 1H) 6.97 (s, 1H) 7.36 (d, J=8.44 Hz, 2H) 7.89 (d, J=8.80 Hz, 2H) 7.95 (s, 1H) 8.42 (s, 1H) 8.68 (s, 1H) 8.91 (br. s, 1H) 10.23 (s, 1H) 12.47 (br. s, 1H) 13.19 (br. s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([O:8][CH2:9]CCC)=[O:7])(=[O:3])[CH3:2]>CC1C=CC=CC=1C>[C:1]([NH:4][C:5](=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCOC(=O)C(=Cc1ccccc1)NC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)C(=Cc1ccccc1)NC(C)=O

Procedure:
Following the procedure of step (iv) of Example 1 but using a 300-ml portion of the o-xylene solution of butyl α-acetamidocinnamate as obtained in step (iii) of Example 8 in place of the o-xylene solution of methyl α-acetamidocinnamate, the hydrogenation reaction was carried out in the same manner as in said step (iv) of Example 1. The conversion of butyl α-acetamidocinnamate was 100 percent and the selectivity toward N-acetyl-DL-phenylalanine butyl ester 99 mole percent. The palladium-on-carbon catalyst was filtered off from the reaction mixture, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give 32 g of N-acetyl-DL-phenylalanine butyl ester.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:5][C:4]1([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:17][N:18](CCO)[CH3:19]>>[CH2:1]([CH:3]1[CH2:5][C:4]1([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([O:8][CH2:9][CH2:10][N:18]([CH3:19])[CH3:17])=[O:7])[CH3:2]
Reactant: CN(C)CCO
Reactant: CCOC(=O)C1(c2ccccc2)CC1CC
Product: CCC1CC1(C(=O)OCCN(C)C)c1ccccc1

Procedure:
In accordance with the procedure described in Example IV, ethyl 2-ethyl-1-phenylcyclopropane-1-carboxylate was reacted with N,N-dimethylaminoethanol to obtain 2-(N,N-dimethylamino)ethyl 2-ethyl-1-phenylcyclopropane-1-carboxylate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][C:17]=1[S:26]([NH:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][O:4][CH2:3][C:2]([F:1])([F:13])[F:14])[N:11]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Cl
Reactant: Nc1cccc(COCC(F)(F)F)n1
Product: O=S(=O)(Nc1cccc(COCC(F)(F)F)n1)c1cc(C(F)(F)F)ccc1Cl

Procedure:
This material was prepared in analogy to example 1 from 6-(2,2,2-Trifluoro-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 2-chloro-5-(trifluoromethyl)- benzenesulfonyl chloride (0.119 g) as alight yellow solid (0.123 g). MS (ESI−): 447.0 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].[O:10]=[C:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C([Li])CCC>>[OH:10][C:11]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][OH:9])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: OCc1ccccc1Br
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccccc2CO)C1

Procedure:
The object product (1.6 g, 30%) was obtained in the same manner as in Example 14(1) and using (2-bromophenyl)methanol (3.3 g), tert-butyl 3-oxopiperidine-1-carboxylate (3.5 g) and n-butyllithium (1.6 M hexane solution, 23 mL).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[C:18]1([C:24]([OH:26])=O)[CH2:23][CH2:22][CH2:21][CH2:20]C=1>>[C:18]1([C:24]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[NH:6][C:7]([C:9]4[CH:10]=[CH:11][C:12]([NH:15][C:24]([C:18]5[CH2:23][CH2:22][CH2:21][CH:20]=5)=[O:26])=[CH:13][CH:14]=4)=[N:8][C:4]=3[CH:3]=2)=[O:26])[CH2:20][CH2:21][CH2:22][CH:23]=1
Reactant: Nc1ccc(-c2nc3ccc(N)cc3[nH]2)cc1
Reactant: O=C(O)C1=CCCCC1
Product: O=C(Nc1ccc(-c2nc3cc(NC(=O)C4=CCCC4)ccc3[nH]2)cc1)C1=CCCC1

Procedure:
Compound 182 was prepared according to the procedure similar to that described in Scheme III from 5-amino-2-(4-aminophenyl)benzimidazole and 1-cyclohexenecarboxylic acid. [M+H]+ calcd for C25H24N4O2: 413.20; found: 412.96.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]([CH3:20])[CH2:8]1.[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:9]([CH3:20])[CH2:8]1)=[O:48])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC1CN(c2c(N)cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 20 h
Yield: 32.6 %

Procedure:
To a solution of tert-butyl (±)-4-(4-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (300 mg, 0.83 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (294 mg, 0.83 mmol), HATU (410 mg, 1.08 mmol) in DMF (15 mL) was added TEA (2 mL). The mixture was stirred at 30° C. for 20 hours, poured into water (100 mL), and extracted with EtOAc (40 mL×3). The combined organic layers was washed with water (50 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by preparative HPLC to give tert-butyl (±)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate as white solid (190 mg, 33%). MS (ESI) m/z: 702 [M+H+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(N(CC)CC)C.C(O)(=O)C.O>CS(C)=O.C(OCC)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14]
Reactant: OCCCCCCOC1CCCCO1
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=CCCCCCOC1CCCCO1
Yield: 64.5 %

Procedure:
Pyridine-sulphur trioxide complex (17.1 g., 0.108 mole) in dimethylsulphoxide (90 ml.) was added dropwise to a mixture of 6-(2-tetrahydropyranyloxy)-hexanol (7.2 g., 0.036 mole) and triethylamine (27 g., 0.27 mole) in dimethylsulphoxide (90 ml.) at 25°C. The mixture was stirred for a further hour, then 2N acetic acid (100 ml.), water (200 ml.) and diethyl ether (500 ml.) added successively, the layers separated and the aqueous layer extracted with diethyl ether. The combined ether solutions were washed quickly with 2N hydrochloric acid, aqueous sodium carbonate and then water, and dried over sodium sulphate. The solvent was evaporated and the residue distilled under reduced pressure to give 6-(2-tetrahydropyranyloxy)hexanal (4.65 g., 63%), b.p. 75°-105°C./0.15 mm.Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:28]=[C:27]([N:29]=[C:30]=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:28]=[C:27]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]3[C:15]4[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=4[N:9]=[CH:8][CH:7]=3)[CH:3]=2)=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)cnc34)c2)n(-c2ccccc2)n1

Procedure:
Method F2 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a slightly yellow solid (97 mg, 62%).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)OC1CCc2c(N)cccc21
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A solution of 10.0 g (0.045 mole) of 4-nitro-1-indanyl acetate in 200 mL of ethanol was mixed with 0.1 g of platinum oxide in 20 mL of ethanol, and the mixture was contacted with hydrogen in a Parr hydrogenator. Upon complete uptake of hydrogen, the reaction mixture was allowed to stand for 16 hours. The platinum oxide was removed by filtration through diatomaceous earth, and the filter cake was washed with ethanol. The ethanol washings were combined with the filtrate, and the whole was concentrated under reduced pressure to give 8.4 g of 4-amino-1-indanyl acetate as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=2)[CH2:12]1)[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.[F:32][C:33]([F:46])([F:45])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:8][CH2:9][CH3:10])[C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:21][S:41]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][C:33]([F:32])([F:45])[F:46])=[CH:40][CH:39]=3)(=[O:43])=[O:42])[CH:17]=2)[CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccc(CC(F)(F)F)cc1
Reactant: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(N)ccc2C1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(NS(=O)(=O)c3ccc(CC(F)(F)F)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
((S)-6-Amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-carbamic acid tert-butyl ester (720 mg, 2.37 mmol) was dissolved in tetrahydrofurane (50 ml). Then, dimethylamino pyridine (100 mg, 0.82 mmol) and 4-(2,2,2-trifluoro-ethyl)benzenesulfonyl chloride (761 mg, 2.37 mmol) were added and the reaction mixture was stirred for 30 minutes at room temperature. The solvent was evaporated under reduced pressure, the residue treated with water and diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give the crude product (1.22 g, 95% purity, 93% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[OH:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10](=[O:19])[CH:11]=[CH:12][C:13]2=[O:18]>C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3][C:4]([O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10](=[O:19])[CH:11]=[CH:12][C:13]2=[O:18])=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: O=C1C=CC(=O)c2c(O)cccc21
Solvent: CCN(CC)CC
Product: O=C(CCCl)Oc1cccc2c1C(=O)C=CC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of triethylamine (1.4 ml) and 1.27 g. of 3-chloropropionylchloride in 5 ml. of DCNM was added to a solution of 1.73 g. of 5-hydroxy-1,4-naphthoquinone. The reaction mixture was stirred for 2 hours at room temperature. The solution was filtered and concentrated to a small volume and chromatographed on a silica gel column (ethylacetate-cyclohexane-DCM) to give 741 mg. of desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].[CH2:21](OC(OCC)OCC)C>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[CH:21][N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[F:20])[C:5]=3[C:4]=2[CH:3]=1
Reactant: Nc1cnc2ccc(F)cc2c1Nc1ccccc1F
Reactant: CCOC(OCC)OCC
Product: Fc1ccc2ncc3ncn(-c4ccccc4F)c3c2c1

Procedure:
200 mg (0.74 mmol) 6-fluoro-N4-(2-fluoro-phenyl)-quinoline-3,4-diamine (Example 19e) in 8 ml triethylorthoformate are heated at 160° C. for 3 h. The cold solution is evaporated to dryness, and the residue is dissolved in hot ethyl acetate. By adding hexane to this solution, the title compound precipitates. The compound is filtered off and dried overnight at 60° C. (high vacuum). mp: 162-163° C.; MS: 282 (M*+1); HPLC: tret=7.26 min (Grad 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:32])[CH:24]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 83.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), m-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.057 g (83%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(=O)(O)[O-].[Na+]>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 4-(3-(piperidin-1-yl)propoxy)benzaldehyde (WO 02/12214 A2) (1.90 g, 7.68 mmol) in dichloromethane (25 ml) was added 1-N tert butoxy carbonyl piperazine (1.57 g, 8.45 mmol) followed by acetic acid (1 ml), and the reaction stirred for 1 hour at room temperature, then treated with sodium triacetoxy borohydride (2 g, 9.61 mmol) and stirred for 16 hours at room temperature. The reaction was then diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane was then washed sequentially with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo to yield a residue which was purified using silica gel chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound (1.586 g, 50%); MS (ES+), m/e 418 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].C(S(C1C2C(=CC=CC=2)NN=1)(=O)=O)(C)C>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9][N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: CC(C)S(=O)(=O)c1n[nH]c2ccccc12
Product: CS(=O)(=O)CCCn1c(Cn2nc(S(C)(=O)=O)c3ccncc32)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared in analogy to Example 1-9 by using 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole and 3-(isopropylsulfonyl)-1H-indazole.
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[C:9]1([CH:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:16][NH:17][C:18]2[N:19]=[CH:20][NH:21][C:22]=2C(N)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl.CO>[C:9]1([CH:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:16][N:17]2[C:18]3[N:19]=[CH:20][NH:21][C:22]=3[C:4](=[O:5])[NH:6][C:7]2=[S:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)N=C=S
Reactant: NC(=O)c1[nH]cnc1NCC(c1ccccc1)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(=S)n(CC(c2ccccc2)c2ccccn2)c2nc[nH]c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 11.4 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.12 mL, 0.99 mmol) was added to 4-[(2-phenyl-2-pyridin-2-ylethyl)amino]-1H-imidazole-5-carboxamide (0.28 g, 0.9 mmol, obtained from Example 23(a)) in dry dichloromethane (10 mL) and dry methanol (0.11 mL). The mixture was stirred for 5 h and then concentrated, redissolved in aqueous potassium hydroxide (1.2 N, 7 mL) and heated at 80° C. for 3 h. After cooling to r.t., pH was adjusted to 7 using hydrochloric acid (2 N). The mixture was filtered and the solid was purified using preparative HPLC, giving the title compound 36 mg (11% yield) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=2)=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 3-chloro-4-fluoro phenyl isocyanate (0.045 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 52 as a colorless solid (0.067 g, 54%). LCMS m/z (%)=485 M+H+ (81Br 37Cl, 30), 483 M+H+ (81Br 35Cl, 100), 481 M+H+ (79Br 35Cl, 72), 1H NMR (400 MHz, CDCl3) δ: 7.7 (s, 1H), 7.4 (d, J=1.8 Hz, 1H), 7.3 (d, J=1.8 Hz, 1H), 7.25 (s, 1H), 7.1-6.8 (m, 3H), 4.2 (m, 1H), 3.8 (s, 3H), 1.5 (d, J=6.61 Hz, 3H), 1.3 (d, J=6.61 Hz, 3H).