Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][F:35])=[CH:27][CH:26]=2)[C:21](O)=[O:22])=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:36][O:37][CH2:38][C@@H:39]([NH2:41])[CH3:40].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@H:20]([NH:19][C:17]([C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][N:11]2[S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:9])=[O:10])=[O:18])[C:21](=[O:22])[NH:41][C@@H:39]([CH3:40])[CH2:38][O:37][CH3:36])=[CH:26][CH:27]=1
Reactant: COC[C@H](C)N
Reactant: O=C(N[C@@H](Cc1ccc(OCCCF)cc1)C(=O)O)C1CCCCN1S(=O)(=O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC[C@H](C)NC(=O)[C@H](Cc1ccc(OCCCF)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
(S)-2-{[1-(3-Fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-[4-(3-fluoro-propoxy)-phenyl]-propionic acid (compound 18b) (80 mg, 0.16 mmol), (S)-1-methoxy-2-propylamine (14 mg, 0.16 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol) were mixed in dichloromethane (2 mL). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane, washed twice with a saturated aqueous sodium bicarbonate solution, and the organic layer was dried over magnesium sulfate. After manual filtration and subsequent concentration the resulting oil was chromatographed on silica gel (dichloromethane/methanol, 9/1) on silica gel to provide 66 mg (72%) of the title compound. MS: m/e 582.2 (M+H). 1H NMR (300 MHz, d6-DMSO): δ0.75-1.60 (m, 9H), 1.85-2.15 (m, 3H), 2.75 (m, 1H), 2.85 (m, 1H), 3.10 (m, 1H), 3.20 (m, 1H), 3.60 (d, 1H, J=12 Hz), 3.85 (m, 1H), 4.00 (t, 2H, J=6 Hz), 4.30 (q, 1H J=7.5 Hz), 4.50 (m, 2H), 4.65 (t, 1H, J=6 Hz), 6.85 (d, 2H, J=9 Hz), 7.15 (d, 2H, J=9 Hz), 7.40 (m, 4H), 7.75 (d, 1H, J=9 Hz), 7.90 (d, 1H, J=6 Hz).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(Cl)cc1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (76 mg, 91%), MS (ISP) m/z=336.4 [(M+H)+], mp 245.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:50][CH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:50][CH2:51][CH2:52][CH2:53][N:54]6[CH2:59][CH2:58][O:57][CH2:56][CH2:55]6)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: NCCCN1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCCCN4CCOCC4)cc3)cn2)cc1
Yield: 75.2 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (50.0 mg, 0.0758 mmol) obtained in Step A in Example 1-D-19 and N-(3-aminopropyl)morpholine (22.1 μl, 0.152 mmol) instead of 3-(aminomethyl)pyridine, amidation was conducted in the same manner as Step B in Example 1-D-19, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(3-morpholin-4-yl-propyl)-benzamide as a yellow solid (44.8 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-93) as a yellow powder (29.3 mg, 71%).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8](C)[C:9]1([C:21](O)=[O:22])[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])[CH:2]([CH3:4])[CH3:3].S(O)(O)(=O)=O.[CH2:30]([N:32]([CH2:40][CH3:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:31].[CH3:42]CN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:40]([N:32]([CH2:30][CH3:31])[C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:21]([C:9]2([NH:8][C:6](=[O:7])[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:18][CH2:17][C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:22])=[C:35]([CH3:42])[CH:34]=1)[CH3:41]
Reactant: COc1cccc2c1CC(C(=O)O)(N(C)C(=O)OCC(C)C)CC2
Reactant: CCN(CC)CC
Reactant: CCN(CC)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)OCC(C)C)CCc3cccc(OC)c3C2)c(C)c1
Reaction time: 8 h
Yield: 40 %

Procedure:
The acid from Example 33F was dissolved in DMF (6.0 mL). N,N-diethyl-benzene-1,4-diamine sulfate (786 mg, 3.0 mmol), Et3N (1.0 g, 10 mmol), and TBTU (963 mg, 3.0 mmol) were added and the resulting mixture was stirred overnight and purified by column chromatography to provide the titled compound (680 mg, 40% over two steps). 1H NMR (400 MHz, DMSO-D6) δ 9.07 (s, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.07 (t, J=7.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.68 (d, J=7.2 Hz, 1H), 6.60 (d, J=8.8 Hz, 2H), 3.78 (s, 3H), 3.76 (m, 2H), 3.27 (q, J=6.8 Hz, 4H), 3.12 (d, J=17.6 Hz, 1H), 2.87 (d, J=16.0 Hz, 1H), 2.85 (s, 3H), 2.64 (m, 2H), 2.32 (m, 1H), 2.19 (m, 1H), 1.80 (m, 1H), 1.05 (t, J=6.8 Hz, 6H), and 0.85 (d, J=6.4 Hz, 6H). MS (ESI) positive ion 482 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:19][C:20](=[O:36])[O:21][CH2:22][C:23]1([CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[N:30]=2)[CH2:26][CH2:25][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C.CCCCCC>ClCCl>[O:13]=[C:3]([NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[C:2]([C@@H:14]([NH:19][C:20](=[O:36])[O:21][CH2:22][C:23]1([CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[N:30]=2)[CH2:26][CH2:25][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1]
Reactant: CCCC[C@H](NC(=O)OCC1(COc2ccnc(Cl)n2)CCC1)C(O)C(=O)N[C@H](C)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCC[C@H](NC(=O)OCC1(COc2ccnc(Cl)n2)CCC1)C(=O)C(=O)N[C@H](C)c1ccccc1
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
To a solution of 0.150 g (0.289 mmol) of (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate in 2.0 mL of dichloromethane was added 0.031 g (0.375 mmol) of sodium bicarbonate followed by the addition of 0.159 g (0.375 mmol) of Dess-Martin periodinane. The reaction was stirred for 15 min and then poured directly onto a column of silica gel eluting with ethyl acetate:hexane (1:1) to afford 0.1 g (67%) of (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methyl (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.31 (m, 6 Hz, 1H), 7.41-7.29 (m, 5H), 7.13 (d, J=7 Hz, 1H), 6.69 (d, J=6 Hz, 1H), 5.29 (d, J=7 Hz, 1H), 5.18-5.08 (m, 2H), 4.41 (s, 2H), 4.20 (s, 2H), 2.07-1.71 (m, 7H), 1.56 (d, J=7 Hz, 3H), 1.26-1.32 (m, 5H), 0.88 (t, J=6 Hz, 3H). LC-MS m/z 517 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:18][Li]>C(OCC)C>[CH2:1]([N:5]1[C:9]([CH:10]([OH:11])[CH3:18])=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]C
Reactant: CCCCn1c(C=O)cnc1-c1ccccc1
Solvent: CCOCC
Product: CCCCn1c(C(C)O)cnc1-c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of aldehyde 102 (230 mg) in diethyl ether (30 mL) is placed in a separatory funnel and treated with a solution of methyl lithium (1.4 M in THF, 1.5 mL). After 10 min, the solution is washed with ammonium chloride solution (1 M, 20 mL), dried (Na2SO4) and concentrated. The resulting dark oil is purified by preparative TLC (10% MeOH/CHCl3) to provide compound 107 as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=2 Hz, 2H), 7.4 (m, 3H), 7.01 (s, 1H), 4.86 (q, J=7 Hz, 1H), 4.18 (m, 1H), 4.0 (m, 1H), 1.63 (d, J=6.6 Hz, 3H), 1.63 (m, 2H), 1.23 (m, 2H), 0.81 (t, J=7 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[CH:7]=1)=O)C.[NH3:26]>CCO>[Cl:25][C:20]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[C:6]([C:4]([NH2:26])=[O:3])[O:10][N:9]=3)=[CH:12][CH:13]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3cccnc3Cl)cc2)no1
Reactant: N
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc(OCc3cccnc3Cl)cc2)no1
Reaction time: 8 h
Yield: 14 %

Procedure:
3-[4-(2-Chloro-pyridin-3-ylmethoxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (which may be prepared as described in Preparation of Intermediate 11; 57 mg, 0.16 mmol) was taken up in 2M NH3 in EtOH. The mixture was stirred overnight, transferred to a 20 mL scintillation vial and evaporated after several hours at room temperature. The residue was purified twice by chromatography, eluting first with 35-80% EtOAc/hexanes and then with 50-90% EtOAc/hexanes to give 3-[4-(2-chloro-pyridin-3-ylmethoxy)-phenyl]-isoxazole-5-carboxylic acid amide (7.2 mg, 14%). HRMS Calcd. for C16H13ClN3O3 (M+H)+, 330.0640. Found: 330.0637.
Reaction SMILES: [N+](C1C=COC2C=1S(=O)(=O)NCC2)([O-])=O.Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=1[S:26]([NH:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27].[H][H]>CO.[Ni]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]2[O:32][CH2:31][CH2:30][NH:29][S:26](=[O:28])(=[O:27])[C:18]=2[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCO)c1
Reactant: [H][H]
Agent: [Ni]
Agent: O=[N+]([O-])C1=C2C(CCNS2(=O)=O)OC=C1
Solvent: CO
Product: Nc1ccc2c(c1)S(=O)(=O)NCCO2
Temperature: 0 °C

Procedure:
244 g of 8-nitro-3,4-dihydro-(2H)-5,1,2-benzoxathiazine 1,1-dioxide, which is accessible by an intramolecular condensation reaction from 2-chloro-5-nitro-N-(2-hydroxyethyl)-benzenesulphonamide (DOS (German Published Specification) 1,670,759), are suspended in 600 ml of methanol and are reduced in the presence of 3 g of freshly prepared Raney nickel as catalyst by injecting three times the equimolar amount of hydrogen in an autoclave at 50° C. When the reduction is complete, the catalyst is removed from the hot reaction solution, from which the amino compound crystallizes out in fine flakes after cooling to 0° C. 205 g of 8-amino-3,4-dihydro-(2H)-5,1,2-benzoxathiazepine 1,1-dioxide of the formula ##STR17## melting point 179° C. are obtained after filtering off with suction and drying.
Reaction SMILES: [CH3:1][C:2]1([CH3:56])[C:10]2=[CH:11][C:12]3[N:13]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:34]6[C:46]7[CH:45]=[C:44]8[C:47]([CH3:55])([CH3:54])[C:48]9[C:53]([C:43]8=[CH:42][C:41]=7[C:40]7[C:35]6=[CH:36][CH:37]=[CH:38][CH:39]=7)=[CH:52][CH:51]=[CH:50][CH:49]=9)=[CH:30][CH:29]=5)=[CH:24][CH:23]=4)[C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.C1C(=O)N([Br:64])C(=O)C1.O>C1COCC1>[Br:64][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:22]1[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31]([N:34]4[C:46]5[CH:45]=[C:44]6[C:47]([CH3:55])([CH3:54])[C:48]7[C:53]([C:43]6=[CH:42][C:41]=5[C:40]5[C:35]4=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:52][CH:51]=[CH:50][CH:49]=7)=[CH:32][CH:33]=3)=[CH:24][CH:23]=1)[C:12]1[CH:11]=[C:10]3[C:2]([CH3:56])([CH3:1])[C:3]4[C:8]([C:9]3=[CH:21][C:20]2=1)=[CH:7][CH:6]=[CH:5][CH:4]=4
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccccc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccc(Br)cc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21
Reaction time: 4 h

Procedure:
9.42 g (13.1 mmol) of 4,4′-bis(12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-10-yl)biphenyl are initially introduced in 77 ml of THF. A solution of 2.36 g (13.2 mmol) of NBS in 25 ml of THF is subsequently added dropwise at −15° C. with exclusion of light, allowed to come to room temperature and stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot ethanol and filtered off with suction. The yield is 7.5 g (9.4 mmol, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[S:30][C:29]([C:31]3([O:35]COC)[CH2:34][CH2:33][CH2:32]3)=[N:28][CH:27]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][C:12]=3[O:24][CH3:25])[NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[C:3]([C:26]2[S:30][C:29]([C:31]3([OH:35])[CH2:34][CH2:33][CH2:32]3)=[N:28][CH:27]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:21])[CH3:22])=[CH:13][C:12]=3[O:24][CH3:25])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)cc5OC)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: COc1cc(NC(=O)CN(C)C)ccc1-c1cc2c(-c3cnc(C4(O)CCC4)s3)c(Cl)cnc2[nH]1

Procedure:
The title compound was prepared as described in Example 22E, substituting N-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methoxyphenyl)-2-(dimethylamino)acetamide (Example 68D) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (500 MHz, DMSO-d6) ppm 12.10 (s, 1H) 9.89 (s, 1H) 8.30 (s, 1H) 8.22 (s, 1H) 7.81 (d, 1H) 7.61 (d, 1H) 7.44 (dd, 1 H) 6.97 (d, 1H) 6.67 (s, 1H) 3.89 (s, 3H) 3.10 (s, 2H) 2.63 (m, 2H) 2.41 (m, 2H) 2.30 (s, 6H) 1.97 (m, 2H); MS ESI(+) m/z 512.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:20]1[CH2:22][CH2:21]1)([CH:17]1[CH2:19][CH2:18]1)[OH:16].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:23](=[O:24])[O:16][C:15]([CH:17]4[CH2:19][CH2:18]4)([CH:20]4[CH2:21][CH2:22]4)[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(O)(C1CC1)C1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C(C2CC2)(C2CC2)O1

Procedure:
The title compound was prepared according to Example 41 from (4-amino-3′-chloro-biphenyl-3-yl)-dicyclopropyl-methanol and 1,1′-carbonyldiimidazole. Yellow solid: mp 198-200° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.72 (bs, 1H), 7.67 (bs, 1H), 7.62 (m, 2H), 7.48 (t, 1H, J=7.88 Hz), 7.40 (d, 1H, J=8.04 Hz), 6.94 (d, 1H, J=8.27 Hz), 1.55 (m, 2H), 0.5 (m, 6H), 0.28 (m, 2H); MS (EI) m/z 339 (M+, 40%); Anal. Calc. For C20H18ClNO2: C, 70.69; H, 5.34 N, 4.12. Found: C, 69.38; H, 5.07; N, 4.02.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[C:12]2S)[CH2:8][CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:21]([O-:24])([OH:23])=[O:22].[OH-].[Na+]>O>[N+:21]([O-:24])([OH:23])=[O:22].[CH:1]1([CH:7]([N:11]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[CH:12]2)[CH2:8][CH2:9][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCC(C1CCCCC1)n1c(C(=O)OC)cnc1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCCC(C1CCCCC1)n1cncc1C(=O)OC
Yield: 82.4 %

Procedure:
A solution of 30 parts of methyl 1-(1-cyclohexylbutyl)-2-mercapto-1H-imidazole-5-carboxylate in 150 parts of concentrated nitric acid and 100 parts of water was stirred for 1 hour at room temperature (intense reaction). The whole was cooled in crushed ice and treated with a sodium hydroxide solution. The product was extracted with 1,1'-oxybisethane. The extract was washed twice with water, dried, filtered and evaporated. The residue was converted into the nitrate salt in 2,2'-oxybispropane. The salt was filtered off and dried, yielding 27 parts (82.4%) of methyl 1-(1-cyclohexylbutyl)-1H-imidazole-5-carboxylate mononitrate; mp. 128.9° C. (compound 26).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[N:11]1([CH2:17][CH2:18][NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][CH:21]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O=P(Cl)(Cl)Cl>[Cl:10][C:5]1[C:6]([Cl:9])=[C:7]2[N:8]=[C:24]([C:23]3[CH:27]=[CH:28][C:20]([NH:19][CH2:18][CH2:17][N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:21][CH:22]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=C(O)c1ccc(NCCN2CCOCC2)cc1
Reactant: Nc1ncc(Cl)c(Cl)c1N
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cnc2[nH]c(-c3ccc(NCCN4CCOCC4)cc3)nc2c1Cl
Temperature: 105 °C
Yield: 2 %

Procedure:
2,3-Diamino-4,5-dichloropyridine (Example 206a) (0.10 g, 0.56 mmol) and 4-[(2-morpholin-4-ylethyl)amino]benzoic acid (prepared in a manner analogous to Example 206c) (0.14 g, 0.56 mmol) were dissolved in POCl3 (5 ml) and heated to 105° C. for 5 h. The excess of POCl3 was evaporated off and the residue was dissolved in EtOAc and aqueous K2CO3. The aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), evaporated in vacuo and the residue was purified by HPLC-C18, giving the title product (0.006 g, 2%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=O)[C:6]=2[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:18])=O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:31][CH2:30]1>C(N(CC)CC)C.ClCCl.CN(C)C=O>[Cl:18][CH:28]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][O:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][CH2:30]1)[CH2:27][NH:26][S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[CH:2][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:15]
Reactant: NCCN1CCN(CCCOc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1cccc2c(Cl)nccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCC(Cl)N1CCN(CCCOc2ccccc2)CC1)c1cccc2cnccc12
Temperature: 0 °C
Yield: 69 %

Procedure:
To 14.2 g of 1-chloro-5-isoquinolinesulfonic acid were added 142 ml of thionyl chloride and 1 . 42 ml of dimethylformamide. The resultant mixture was heated under reflux for 3 hours and the thionyl chloride was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was dissolved in 100 ml of ice water and adjusted to a pH of 6 with a saturated aqueous sodium carbonate solution, followed by extraction with 100 ml of dichloromethane to obtain a dichloromethane phase. The dichloromethane phase was dropwise added to 100 ml of a dichloromethane solution containing 15.4 g of 1-(2-aminoethyl)-4-[3-(phenoxy)propyl]piperazine and 6.5 g of triethylamine over 30 minutes while cooling with ice. The resultant mixture was stirred at a temperature of 15° C. to 20° C. for 2 hours to carry out a reaction. After completion of the reaction, the reaction mixture was washed with 200 ml of water and dried over anhydrous magnesium sulfate. Then, solvent removal was conducted by distillation under reduced pressure to thereby obtain a residue. The thus obtained residue was subjected to purification by means of a column for chromatography packed with 250 g of silica gel (Wakogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using a mixed solvent of methanol and chloroform (2% methanol) as an eluent, to thereby obtain 19.6 g of 1 -(1-chloro-5-isoquinolinesulfonylaminoethyl)-4-[3-(phenoxy) propyl]piperazine (yield: 69%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].[C:26](Cl)(Cl)=[S:27]>O.C(O)CC>[I:13][C:10]1[CH:11]=[CH:12][C:3]([N:2]=[C:26]=[S:27])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: S=C(Cl)Cl
Reactant: COC(=O)c1cc(I)ccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Solvent: O
Product: COC(=O)c1cc(I)ccc1N=C=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 20 g (0.064 mol) of methyl 2-amino-5-iodobenzoate hydrochloride was added 720 mL of toluene, 180 mL of water, 49 g (0.593 mol) of sodium bicarbonate, and 13.2 mL (0.181 mol) of thiophosgene. The biphasic mixture was stirred at room temperature overnight, diluted with 400 mL of water, and the phases were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to deliver 21.43 g of the title compound, which was used without further purification, 1H NMR (300 MHz, CDCl3): δ3.97 (s,3H); 7.02 (d,1H); 7.81 (dd,1H); 8.30 (d,1H). An analytical sample was prepared by treating 0.30 g of the crude material with 5 mL of n-propanol, followed by the dropwise addition of water. The ensuing precipitate was filtered to deliver 259 mgs of purified methyl 5-iodo-2-isothiocyanatobenzoate, m.p. 60-62° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1cnc(I)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: FC(F)(F)c1ccc(-c2ncc(Br)cn2)cc1
Yield: 60.2 %

Procedure:
5-bromo-2-iodopyrimidine (250 mg), 4-trifluoromethylphenylboronic acid (167 mg), bis(triphenylphosphine)palladium(II) chloride (22 mg) and Na2CO3 (2.1 ml, 1M in H2O) in argon saturated acetonitrile (2.1 ml) was heated under microwave conditions (150° C., 10 minutes). The conversion was monitored and analyzed by HPLC. The crude reaction mixture was concentrated to dryness, then diluted with CH2Cl2, washed with water (3×10 ml), dried over Na2SO4, concentrated under vacuum and purified by chromatography column using CH2Cl2-hexane 1:10 as eluent to give 160 mg of the desired product as a white solid.