Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.O>[CH3:11][S:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)(=[O:14])=[O:13]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A cooled solution of 4′-aminoacetophenon (10 mmol) in pyridine (10 mL) at 0° C. was treated with methanesulfonyl chloride (15 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc several times. The combined organic layers were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes to afford 4′-(Methylsulfonylamino)acetophenone (13-5, LJO-298).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:35]([NH:52][C@H:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(F)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (26 mg, yield 58%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCO
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCO)c1ccccc1
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To a solution of ethanolamine (1.09 g, 17.8 mmol) in THF was added benzoyl chloride (520 mg, 3.60 mmol) dropwise at 0° C. under N2 atmosphere. The reaction mixture was stirred for 10 min and then quenched with 1M HCl. The mixture was then diluted with EtOAc and washed with sat. aq. NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was crystalized to give N-(2-hydroxyethyl)benzamide (593 mg, 97%) as a white crystalline solid. 1H NMR (CDCl3, 300 MHz) δ3.41 (s, 1H), 3.49-3.59 (m, 2H), 3.75 (t, 2H, J=5.2 Hz), 7.10 (s, 1H), 7.32-7.38 (m, 2H), 7.42-7.48 (m, 1H), 7.72-7.76 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:44]3[CH2:43][CH2:42][CH:41]([N:38]4[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]4)[CH2:46][CH2:45]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (200 mg, 0.35 mmol) in DMF (4 mL) was added 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (170 mg, 0.77 mmol), DIEA (134.4 mg, 1.04 mmol), HATU (160 mg, 0.42 mmol). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (25.0% up to 34.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 25.0% in 2 min); Detector, UV 254/220 nm. This resulted in 74.3 mg (32%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide formate as a off-white solid. LCMS (Method 20) [M+H]+=628.2, RT=2.20 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.36-9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.25-5.21 (m, 2H), 4.36-4.29 (m, 1H), 3.98-3.79 (m, 1H), 3.10-3.00 (m, 1H), 2.69-2.51 (m, 1H), 2.49-2.32 (m, 8H), 2.18 (s, 3H), 1.91-1.86 (m, 2H), 1.47-1.41 (m, 1H), 1.39-1.25 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=2)[C:15]([NH:17]C2C=CC(C#N)=CC=2)=[O:16])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:30].[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O.[Na]>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13]([C:28]3[CH:27]=[CH:26][C:14]([C:15]4[NH:30][N:33]=[N:32][N:31]=4)=[CH:13][CH:12]=3)=[C:14]([CH:26]=[CH:27][CH:28]=2)[C:15]([NH2:17])=[O:16])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: [NH4+]
Reactant: N#Cc1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(Cl)c3)c2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NS(=O)(=O)c2cccc(Cl)c2)c1-c1ccc(-c2nnn[nH]2)cc1

Procedure:
A microwave vial was charged with a solution of 3-(3-chloro-benzenesulfonylamino)-N-(4-cyano-phenyl)-benzamide (0.46 g, 1.12 mmol) in dimethylformamide (20.0 ml), ammonium chloride (1.11 g, 21 mmol, 18.5 equiv.) and sodium azide (1.31 g, 20 mmol, 18 equiv.) and irradiated in a microwave oven at 155° C. for 75 min. The mixture was diluted with saturated sodium hydrogenocarbonate and the phases were separated. The aqueous phase was washed with ethyl acetate and the organic phases were discarded. The aqueous phase was acidified with HCl (1N) and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude compound was triturated in dichloromethane and the white solid was filtered and dried under high vacuum. The title compound, MS (ISP): m/e=453.3 (M−H) was obtained as a white solid, 0.40 g (80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:8]1[NH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:7]=1[CH2:6]2.[O:25]=[C:26]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:27][C:28](O)=[O:29].CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]([NH:12][C:11]2[C:7]3[CH2:6][C:5]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:8]=3[N:9]([C:28](=[O:29])[CH2:27][C:26]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:25])[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc2c(cc1OC)-c1[nH]nc(Nc3cccc(F)c3)c1C2
Reactant: O=C(O)CC(=O)N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)CC(=O)N1CCCC1)C2

Procedure:
A mixture of (6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (Compound 14) (0.36, 1.0 mmol), 3-Oxo-3-pyrrolidin-1-yl-propionic acid (Compound 28a) (0.157 g, 1.0 mmole), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.24 g, 1.25 mmol), hydroxybenzo-triazole hydrate (HOBT) (0.17 g, 1.25 mmol) and DIEA (0.220 mL, 1.25 mmol) was stirred in 10 mL DMF over night at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The solvent was removed in vacuo and the crude material was prepped on the Gilson. Lyophilization produced a white powder. MS m/z 465.1 (M+H)+;
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]([OH:16])=O)=[O:10].CN1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>ClCCl.CN(C)C=O>[C:22]1([CH2:21][O:20][C:19]2[CH:18]=[CH:17][C:13]([C:14]([N:32]3[CH2:33][CH2:34][CH2:1][CH2:30][CH2:31]3)=[O:16])=[CH:12][C:11]=2[C:9]([O:8][CH3:7])=[O:10])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1cc(C(=O)O)ccc1OCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.61 ml, 6.99 mmol) was added dropwise to a stirred solution of 3-[(methyloxy)carbonyl]-4-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 49; 400 mg, 1.40 mmol) in dichloromethane (10 ml) and dimethylformamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 h. The solvent was then removed and the residue was dissolved in dichloromethane (5 ml). This mixture was added to a solution of 1-methylpiperazine (525 mg, 5.24 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 2 h. Water (60 ml) was added to the mixture, which was then extracted with dichloromethane (3×60 ml). The organic phase was washed with saturated brine (50 ml), dried over sodium sulfate and evaporated in vacuo to give the crude product. The crude product was loaded onto a silica gel (200 g) column and eluted with dichloromethane/methanol=50:1 to yield the title compound as a colourless oil. 450 mg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1.CCN(C(C)C)C(C)C>O>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: c1cn[nH]c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(-n2cccn2)n1
Temperature: 120 °C
Yield: 81.9 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) (0.49 mg, 1.22 mmol), 1H-pyrazole (1.0 g, 14.7 mmol), and DIPEA (3 mL) was heated to 120° C. for 40 min, cooled to 20° C., and diluted with water (50 mL). The resulting precipitate was collected by filtration, washed with water, and dried. Chromatography on silica, eluting with CH2Cl2/EtOAc (4:1), gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl]-1H-benzimidazole (428 mg, 82%): mp (CH2Cl2/hexanes) 274-277° C.; 1H NMR (DMSO-d6) δ 8.79 (dd, J=2.8, 0.5 Hz, 1H), 8.14 (dd, J=8.3, 0.5 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.88 (t, J=52.8 Hz, 1H), 7.49 (t, J=8.2 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.70 (dd, J=2.8, 1.5 Hz, 1H), 4.01 (m, 2H), 4.00 (s, 3H), 3.93 (m, 2H), 3.80-3.75 (m, 4H); Anal. Calcd. for C19H18F2N8O2: C, 53.3; H, 4.2; N, 26.2. Found: C, 53.1; H, 4.1; N, 25.9%.
Reaction SMILES: [SH:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[NH2:8][C:9]1[CH:14]=[N:13][C:12]([CH3:15])=[CH:11][N:10]=1.Cl[C:17]1[C:18]2[N:26]=[C:25](Cl)[CH:24]=[CH:23][C:19]=2[N:20]=[CH:21][N:22]=1>>[CH3:15][C:12]1[N:13]=[CH:14][C:9]([NH:8][C:17]2[C:18]3[N:26]=[C:25]([S:1][C:2]4[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=4)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[N:10][CH:11]=1
Reactant: Cn1ccc(S)n1
Reactant: Cc1cnc(N)cn1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: Cc1cnc(Nc2ncnc3ccc(Sc4ccn(C)n4)nc23)cn1

Procedure:
The compound of Example 46 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 3-mercapto-1-methylpyrazol, 2-amino-5-methylpyrazine and 4,6-dichloropyrido-[3,2-d]pyrimidine.
Reaction SMILES: C([C:4]12[CH2:19][CH2:18][CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)C=C.ClC1C=CC=[C:23]([C:27]([O:29]O)=O)[CH:22]=1>CCOCC.C1C=CC=CC=1>[O:29]1[CH2:27][CH:23]1[CH2:22][C:6]1[C:5]2[CH:4]3[CH2:19][CH2:18][CH:11]([C:12]4[C:17]3=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC12CCC(c3ccccc31)c1ccccc12
Solvent: c1ccccc1
Solvent: CCOCC
Product: c1ccc2c(c1)C1CCC2c2c(CC3CO3)cccc21

Procedure:
A solution of 9-β-propenyl-9,10-dihydro-9,10-ethanoanthracene (1.1 g) and m-chloroperbenzoic acid (1.6 g) in ether was stirred at room temperature for 5 days. The solution was diluted with benzene, washed with aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-β,γ-epoxypropyl-9,10-dihydro-9,10-ethanoanthracene as an oil, I.R., 3070, 3040, 3020, 2860, 1263, 1140, 1033, 830, 760, 680, 630 cm-1.
Reaction SMILES: [H-].[Na+].Cl.Cl[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17](=[O:25])[C:16]2=[CH:26][S:27][CH:28]=[C:15]12>CN(C)C=O>[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[C:17](=[O:25])[C:16]2=[CH:26][S:27][CH:28]=[C:15]12
Reactant: ClCCN1CCOCC1
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cscc2C(=O)N(CCN2CCOCC2)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.31 g. of 55% sodium hydride-mineral oil dispersion and 0.65 g. of N-(2-chloroethyl)morpholine hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.40 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to dryness and the solid residue is recrystallized from ethyl acetate-hexane to give white crystals, m.p. 109°-111°C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl-:7].[K+].[Pt+2:9].[Cl-:10].[Cl-]>O>[Pt+2:9].[Cl:7][C@@H:3]1[C@H:2]([NH2:1])[CH2:6][CH2:5][N:4]1[Cl:10]
Reactant: [Cl-]
Reactant: N[C@@H]1CCNC1
Agent: [Pt+2]
Agent: [K+]
Solvent: O
Product: N[C@@H]1CCN(Cl)[C@@H]1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.7 %

Procedure:
(3R)-3-Aminopyrrolidine (400 mg) prepared in Reference Example 1-(3) is dissolved in water (200 ml) and thereto is added platinum (II) potassium chloride (2.0 g), and the mixture is stirred at room temperature for 20 hours. The precipitated solid is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue is added water (3 ml), and the resulting crystals are separated by filtration and washed with water and acetone to give cis-dichloro-(3R)-3-aminopyrrolidine platinum (II) (1.28 g) as pale yellow crystal. The physical properties of the cis-dichloro-(3R)-3-aminopyrrolidine platinum (II) thus obtained are identical with those of the cis-dichloro-(3R)-3-aminopyrrolidine platinum (II) as obtained in the above (1-A).
Reaction SMILES: O.[N+:2]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=4)=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)=[CH:14][CH:15]=2)=[CH:38][CH:39]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CCCCCCc3ccc(Cc4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cc2ccc(CCCCCCc3ccc(Cc4ccc(N)cc4)cc3)cc2)cc1
Yield: 84.5 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 3.5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 35.0 g of 1,6-bis(4-(4-nitrobenzyl)phenyl)hexane in 200 milliliters of tetrahydrofuran were introduced, and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Crystals were dissolved in chloroform, subjected to a column chromatography treatment with active alumina and silica gel, and thereafter the solution was reconcentrated to give a concentrate, which was then recrystallized from a mixed solvent of toluene and denatured ethanol, to obtain 26.1 g of 1,6-bis(4-(4-aminobenzyl)phenyl)hexane. Melting point was from 111.4° to 112.2° C.
Reaction SMILES: [C:1]([C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=O)=[CH:9][CH:8]=1)([CH3:5])[CH3:4])#[N:2].[CH3:19][NH2:20]>CO>[C:1]([C:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([NH:20][CH3:19])=[O:17])=[CH:11][CH:12]=1)([CH3:4])[CH3:5])#[N:2]
Reactant: CN
Reactant: COC(=O)CCc1ccc(NC(C)(C)C#N)cc1
Solvent: CO
Product: CNC(=O)CCc1ccc(NC(C)(C)C#N)cc1
Temperature: 0 °C

Procedure:
To a solution of compound 37 (20 mg, 0.08 mmol) in CH3OH (3 mL) was added dropwise a solution of the CH3NH2 in CH3OH (3 mL) at 0° C. with stirring. The reaction mixture was stirred at 0° C. for 6 h. The ice-water was added into the reaction mixture. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 38 (25 mg) as a light yellow oil. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.09 (d, 2H, J=8.2 Hz), 6.86 (d, 2H, J=8.2 Hz), 2.90 (t, 2H, J=7.4 Hz), 2.77 (d, 3H, J=4.8 Hz), 2.43 (t, 2H, J=7.4 Hz), 1.68 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9]2)[C:3]=1[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.C(N=[C:32]=[O:33])C>N1C=CC=CC=1>[CH3:7][N:6]1[C:2]2[NH:1][C:32](=[O:33])[C:24]3[CH2:25][CH2:26][CH2:27][CH2:28][C:23]=3[C:3]=2[C:4]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9]2)=[N:5]1
Reactant: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)c(C2=CCCCC2)c1N
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)c2c3c(c(=O)[nH]c21)CCCC3
Yield: 76.9 %

Procedure:
To a stirring solution of EXAMPLE 24D (0.967 g, 2.54 mmol) in pyridine (10 mL) was added ethyl isocyanate (0.6 mL, 7.62 mmol) and the solution heated at reflux for 24 hours. After cooling, the mixture was concentrated and the residue recrystallized from methanol. The white solid was collected by filtration, washed with methanol and dried to give the title compound (794 mg, 77%). 1H NMR (DMSO-d6): 1.66-1.77 (m, 4H), 2.01-2.17 (m, 1H), 2.18-2.27 (m, 1H), 2.37-2.43 (m, 2H), 2.86-2.92 (m, 2H), 3.33-3.46 (m, 1H), 3.49-3.64 (m, 2H), 3.68-3.76 (m, 1H), 3.76 (s, 3H), 3.77-3.85 (m, 1H), 5.08 (s, 2H), 7.29-7.35 (m, 1H), 7.34-7.39 (m, 5H).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.CN(C=O)C.[CH3:29][C:30]1[O:34][N:33]=[C:32]([C@:35]([OH:39])([C:37]#[CH:38])[CH3:36])[CH:31]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[F:23][C:3]1[C:2]([C:38]#[C:37][C@@:35]([OH:39])([C:32]2[CH:31]=[C:30]([CH3:29])[O:34][N:33]=2)[CH3:36])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1nc2n(c1C(F)(F)F)CCOc1cc(F)c(Br)cc1-2
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2C(F)(F)F)no1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared similarly according to Procedure E. To a solution of 10-bromo-9-fluoro-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (73 mg, 0.12 mmol) in a mixture of anhydrous DMF (0.5 mL) and acetonitrile (0.7 mL) were introduced (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol (168 mg, 1.10 mmol), copper(I) iodide (4 mg, 0.02 mmol) and triethylamine (700 mg, 6.92 mmol). The solution was de-oxygenated by bubbling with nitrogen for 5 min, then bis(triphenylphosphine)palladium(II) chloride was added and bubbling continued for a further 5 min. The reaction mixture was warmed to 90° C. for 48 hr under an atmosphere of nitrogen, then allowed to stand at room temperature for a further 24 hr. Following evaporation of the reaction mixture in vacuo, the residue was re-dissolved in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate solution (15 mL). The organic extract was dried over sodium sulfate, filtered and evaporated in vacuo. Purification by silica gel flash column chromatography (heptane/ethyl acetate gradient) furnished a tan solid which was suspended in acetonitrile (0.3 mL), sonicated for 30 seconds, and the solid isolated by suction filtration. Drying on the filter gave the title compound as an off-white solid: 1H NMR (500 MHz, DMSO) δ 1.81 (3H, s), 2.41 (3H, s), 4.50-4.55 (2H, m), 4.58-4.63 (2H, m), 6.35 (1H, d, J=0.63 Hz), 6.60 (1H, s), 7.10 (1H, d, J=10.40 Hz), 7.53 (1H, br. s.), 7.99 (1H, s), 8.63 (1H, d, J=8.20 Hz); 19F NMR (235 MHz, DMSO) δ −54.3, −108.0; LC-MS: m/z 465.05 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[NH2:43][CH:44]1[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NC1CCNCC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 4-amino-1-tert.-butyloxycarbonyl-piperidine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.