Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[C:34](O)(=[O:37])[CH2:35][OH:36]>>[OH:37][CH2:34][C:35]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=[O:36]
Reactant: O=C(O)CO
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)CO)C3)ccc1-2
Yield: 27 %

Procedure:
Following the procedure for 318, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 31 and glycolic acid were reacted. Purification by reverse phase preparative HPLC (Gemini C18 column, gradient 5-98% MeOH in H2O+0.1% HCO2H) gave 397 as a white solid (46 mg, 27%). LCMS: RT=10.33 min, [M+H]+=426. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1H, d, J=8.20 Hz), 8.05 (1H, s), 7.20-7.15 (1H, m), 7.01 (1H, d, J=1.82 Hz), 5.82-5.72 (1H, m), 4.88-4.81 (1H, m), 4.55-4.46 (1H, m), 4.34-4.29 (2H, m), 4.30-4.17 (1H, m), 4.16 (1H, dd, J=9.24, 5.41 Hz), 3.90 (2H, d, J=5.77 Hz), 3.89-3.77 (2H, m), 3.41-3.35 (2H, m), 1.49 (6H, d, J=6.59 Hz)
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:9]=[C:10]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([CH3:37])[N:32]1[C:38]1[N:42]2[CH:43]=[C:44]([O:47][C@H:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[C@@H:51]([NH2:58])[CH2:50][CH2:49]3)[CH:45]=[CH:46][C:41]2=[N:40][N:39]=1.C[C@H]1CCC[C@@H](C)N1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](NC(=O)NC4N(C5C=NN(CCOS(C)(=O)=O)C=5)N=C(C(C)C)C=4)CC3)C=CC2=NN=1>>[C:15]([C:12]([CH3:14])([CH3:13])[C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:58][C@@H:51]2[C:52]3[C:57](=[CH:56][CH:55]=[CH:54][CH:53]=3)[C@H:48]([O:47][C:44]3[CH:45]=[CH:46][C:41]4[N:42]([C:38]([N:32]5[C@H:31]([CH3:30])[CH2:36][CH2:35][CH2:34][C@@H:33]5[CH3:37])=[N:39][N:40]=4)[CH:43]=3)[CH2:49][CH2:50]2)=[O:27])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:9]=1)#[N:16]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C#N)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Agent: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared using Intermediate 20e and Intermediate 3 in an analogous fashion to the procedure described for Intermediate A step d. LCMS (Method 3): Rt 3.61 min, m/z 704.5 [MH+].
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:18][C:17]([F:34])=[CH:16][N:15]=1>C(#N)C>[F:34][C:17]1[CH:18]=[C:19]2[N:20]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]3)[C:1](=[O:2])[NH:13][C:14]2=[N:15][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(F)cnc2N)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncc(F)cc32)CC1
Yield: 39.1 %

Procedure:
Carbonyldiimidazole (1.53 g, 9.41 mmol) was added to a solution of tert-butyl 4-[(2-amino-5-fluoropyridin-3-yl)amino]piperidine-1-carboxylate (0.73 g, 2.35 mmol) in acetonitrile (10 mL) at room temperature. The reaction was stirred until all the starting material was consumed (approximately 2 h) and then the solvent was evaporated in vacuo. The residue was diluted with water, extracted with dichloromethane (3×), dried over magnesium sulfate and then concentrated. The crude product was purified by chromatography (silica gel, 1% to 10% methanol in methylene chloride gradient elution), which gave the title compound (0.309 g). MS 337.2 (M+1)
Reaction SMILES: F[B-](F)(F)F.[N:6]1([O+]=C(N(C)C)N(C)C)[C:10]2C=CC=CC=2N=N1.CN.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:33]=[N:34][N:35]([C@H:37]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:39]([C:49](O)=[O:50])[CH2:38]3)[CH:36]=2)=[CH:28][C:27]=1[C:52]1[O:53][C:54]2[CH:60]=[CH:59][CH:58]=[CH:57][C:55]=2[N:56]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:33]=[N:34][N:35]([C@H:37]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:47])([CH3:48])[CH3:46])=[O:43])[C@H:39]([C:49](=[O:50])[NH:6][CH3:10])[CH2:38]3)[CH:36]=2)=[CH:28][C:27]=1[C:52]1[O:53][C:54]2[CH:60]=[CH:59][CH:58]=[CH:57][C:55]=2[N:56]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)C[C@H]1C(=O)O
Reactant: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1C[C@@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A slurry of benzotriazol-1-yl-[bis(dimethylamino)methylene]oxonium tetrafluoroborate (149 mg) was added to methylamine (0.892 ml, 2M in methanol) and (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (175 mg) and triethylamine (0.883 ml) dissolved in DMF (8 ml) over a period of 10 minutes. The resulting solution was stirred at 25° C. overnight. The mixture was evaporated and a saturated solution of NaHCO3 (50 ml) was added to the mixture, extracted with methylene chloride (50 ml×2), dried over Magnesium sulphate, filtered and evaporated in reduce pressure. The reaction mixture was purified by preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford (2S,4R)-tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-2-(methylcarbamoyl)pyrrolidine-1-carboxylate (60 mg) as a solid. Retention time: 3.44 min Mass spectrum: M+H+ 504
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(C)c(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a slurry of 2-bromo-1,4-dimethylbenzene (10.13 g, 54.7 mmol) in acetic acid (44 mL) at 8° C. (inner temperature) was added a solution of nitric acid (6 mL, 134 mmol) in sulfuric acid (22 mL, 413 mmol) over 45 min; temperature rose to 10° C. After 1 hr, the reaction mixture was poured into ice and stirred, filtered and washed with water to give a light yellow solid. This was triturated with EtOH (10 mL) to give the desired product (4.550 g, 19.78 mmol, 36.1% yield) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][C@@H:14]([C:16]([OH:18])=[O:17])[NH:13][CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:52](O)[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:12][NH:13][C@H:14]([C:16]([O:18][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:17])[CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:25])([F:24])[F:26])[N:3]=1
Reactant: CCCCCCCCO
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Temperature: 25 °C

Procedure:
To a flask equipped with a Dean Stark trap were added (2S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5]decane-2-carboxylic acid (1 g, 1.78 mmol), toluene (25 mL), and p-toluene sulfonic acid monohydrate (336 mg, 1.77 mmol), and n-octanol (690 mg, 5.30 mmol). The reaction mixture was heated to reflux for 48 h, cooled to RT, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (CH2Cl2/MeOH/NH4OH) provided the title compound as a white solid.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[C:6]([F:16])[CH:5]=1.O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:11]1[S:10][C:9]([CH2:8][C:7]2[CH:14]=[CH:15][C:4]([Br:3])=[CH:5][C:6]=2[F:16])=[CH:13][CH:12]=1
Reactant: Fc1cc(Br)ccc1Cc1cccs1
Reactant: BrBr
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc(Br)ccc1Cc1ccc(Br)s1
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of bromine (0.44 ml) in acetic acid (5 ml) was added during 10 minutes to a stirred solution of (4-bromo-2-fluorobenzyl)thiophene (2.33 g) in acetic acid (10 ml). The solution was stirred for 2 hours, then poured into a mixture of water (50 ml) and a 20% w/v solution of sodium metabisulphite (20 ml). The mixture was extracted with ether (2×50 ml), the combined extracts washed with water and saturated brine, and then dried (MgSO4). The solvent was removed by evaporation to give 2-bromo-5-(4-bromo-2-fluorobenzyl)thiophene as an oil; in 72% yield; NMR: 4.04(s,2H), 6.55(d,1H), 6.85(d,1H), 7.07(t,1H), 7.14-7.30(m,2H); m/e, (chemical ionisation) 348(M+); which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)c(Cl)c3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
To a solution of 1-(3,4-dichloro-phenyl)-piperazine (0.14 g, 0.601 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (95 uL, 0.802 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a, d]cyclohepten-7-yl]-propan-2-ol (0.37 g, 1.0 mmol), added in three portions over 2 h. The reaction was then stirred at 80° C. for 18 hours. The reaction was concentrated in vacuum, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound as a white solid (0.15 g, 69%). 1H-NMR (MeOD) δ: 1.55 (6H, s), 2.35-2.65 (8H, m), 3.15-3.25 (4H, m), 5.30 (2H, br s), 6.20 (1H, t), 6.82 (1H, dd), 7.23-7.55 (5H, m), 7.59 (1H, d), 8.50 (1H, dd).
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20](=[O:37])[C:19]=1[CH3:38]>O1CCOCC1.[Pd]>[CH3:36][C:26]([S:32]([CH3:35])(=[O:34])=[O:33])([CH2:25][CH2:24][N:21]1[CH:22]=[CH:23][C:18]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:19]([CH3:38])[C:20]1=[O:37])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(C)(CCn1ccc(I)c(C)c1=O)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(CCn1ccc(-c2ccccc2)c(C)c1=O)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Water (1 mL) was added to a suspension of potassium carbonate (392 mg, 2.84 mg), phenylboronic acid (76.1 mg, 0.624 mmol), and ethyl 4-(4-iodo-3-methyl-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (250 mg, 0.567 mmol) in 1,4-dioxane (5 mL) at ambient temperature. To this mixture was added Pd EnCat™ (154 mg, 0.06 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, filtered, diluted with ethyl acetate and washed with water. To the organic extract was added silica gel and the mixture was concentrated to dryness. The material was purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanoate as an oil. 118.3 mg
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][CH:15]([C:17](O)=[O:18])[CH2:14][N:13]([CH2:20][CH:21]([F:23])[F:22])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28](=[O:31])[CH2:29][CH3:30].C(N(CC)CC)C>CC1CCCO1>[F:22][CH:21]([F:23])[CH2:20][N:13]1[CH2:12][C:11]2([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:25][CH2:24]2)[O:16][CH:15]([C:17](=[O:18])[NH:26][CH2:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)O)O2
Reactant: CCC(=O)CN
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: CCC(=O)CNC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 40 °C
Yield: 60.2 %

Procedure:
To 9-(tert-butoxycarbonyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (418 mg, 1.15 mmol), 1-aminobutan-2-one (156 mg, 1.26 mmol) and propane phosphonic acid anhydride (T3P) (1.095 g, 1.0 mL of 50% w/w, 1.72 mmol) in 2-methyltetrahydrofuran (3.1 mL) was added triethylamine (640 μL, 4.59 mmol) at room temperature. The reaction mixture was then heated at 40° C. for 5 hours. The reaction mixture was cooled quenched with sat. aq. NaHCO3 and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo, then purified by silica gel column chromatography using 0-50% EtOAc in DCM to yield tert-butyl 4-(2,2-difluoroethyl)-2-((2-oxobutyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (300 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 1H), 6.09-5.64 (m, 1H), 4.31 (dd, J=11.0, 3.0 Hz, 1H), 4.21-4.05 (m, 2H), 3.77 (ddt, J=10.9, 7.5, 6.3 Hz, 2H), 3.39-3.17 (m, 2H), 3.14-2.95 (m, 1H), 2.80-2.63 (m, 3H), 2.50 (q, J=7.3 Hz, 2H), 2.41-2.27 (m, 1H), 2.25-2.11 (m, 2H), 1.67-1.51 (m, 3H), 1.46 (s, 9H), 1.13 (t, J=7.4 Hz, 3H). ESI-MS m/z calc. 433.2. found 434.5 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: CN(C1C=CC=CN=1)C.C[Si]([N:14]=[C:15]=[O:16])(C)C.C(Cl)Cl.[CH3:20][S:21]([C:24]1[CH:50]=[CH:49][C:27]([O:28][C:29]2[C:43]([CH:44]3[CH2:48][CH2:47][CH2:46][NH:45]3)=[CH:42][C:32]3[NH:33][C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[N:35][C:31]=3[CH:30]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>O>[CH3:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([O:28][C:29]2[C:43]([CH:44]3[CH2:48][CH2:47][CH2:46][N:45]3[C:15]([NH2:14])=[O:16])=[CH:42][C:32]3[NH:33][C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[N:35][C:31]=3[CH:30]=2)=[CH:49][CH:50]=1)(=[O:22])=[O:23]
Reactant: C[Si](C)(C)N=C=O
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 mg of dimethylaminopyridine and 0.029 ml of trimethylsilyl isocyanate were added to a methylene chloride (1 ml) solution of 17.1 mg of 5-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 162 (step 7), and the reaction liquid was stirred overnight at room temperature. Water was added to the reaction liquid, and extracted with ethyl acetate, and then washed with saturated saline. After dried and concentrated, the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid], and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([OH:40])=[O:39])[CH:33]1[OH:41].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([OH:40])=[O:39])[CH:33]4[OH:41])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: NC1CCCC(C(=O)O)C1O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(C(=O)O)C4O)n3)c3cc(Cl)cnc32)cc1

Procedure:
5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, 65a, (0.30 g, 0.64 mmol), 3-amino-2-hydroxy-cyclohexanecarboxylic acid (0.19 g, 0.97 mmol), iPr2NEt (0.45 mL, 2.58 mmol) in DMF (23.2 mL) solution was heated in microwave at 130° C. for 10 min. The solvent of the reaction mixture was removed under reduced pressure and the residue was purified by preparatory HPLC to give 240 mg of 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-cyclohexanecarboxylic acid, 65b, as a mixture of stereoisomers.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].N1CC=CC1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:23]2[CH2:24][CH:25]=[CH:22][CH2:21]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CCN(CC)CC
Agent: C1=CCNC1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CC=CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (500 mg; 1.2 mmol; 1 eq), is dissolved in anhydrous DCM (30 ml). The reaction is put under nitrogen. Triethylamine (0.34 ml; 2.41 mmol; 2 eq) and 3-pyrroline (166.2 mg; 2.41 mmol; 2 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (600 mg; 99%).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH:13](=O)[C:14]1[CH:24]=[C:21]([O:22][CH3:23])[C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.Cl>>[CH3:23][O:22][C:21]1[CH:24]=[C:14]([CH:15]=[C:16]([O:17][CH3:18])[C:19]=1[OH:20])[CH:13]=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: NNC1=NCCc2ccccc21
Agent: Cl
Product: COc1cc(C=NNC2=NCCc3ccccc32)cc(OC)c1O

Procedure:
In a manner similar to that of Example 4, condensation of 1-hydrazino-3,4-dihydroisoquinoline (10.0 g.) and syringaldehyde (12.5 g.) and treatment of the reaction mixture with hydrochloric acid gave a solid, which was recrystallized from N,N-dimethylformamide-ether, affording 1-[2-(3,5-dimethoxy-4-hydroxybenzylidene)hydrazino]-3,4-dihydroisoquinoline (I: X=3,5-(CH3O)2 -4-HOC6H2, X'=Y=Y'=Z=Z'=H) hydrochloride in two crops (total of 18 g., m.p. 232°-233° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)(=[O:32])=[O:31])=[CH:26][C:25]=1[S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)(=[O:44])=[O:43].[CH3:54][C:55]1[CH:60]=[CH:59][C:58]([SH:61])=[CH:57][CH:56]=1.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1.[CH3:54][C:55]1[CH:60]=[CH:59][C:58]([S:61][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)(=[O:32])=[O:31])=[CH:26][C:25]=2[S:42]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)(=[O:44])=[O:43])=[CH:57][CH:56]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=S(=O)(CCCN1CCOCC1)c1ccc(Cl)c(S(=O)(=O)CCCN2CCOCC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Sc2ccc(S(=O)(=O)CCCN3CCOCC3)cc2S(=O)(=O)CCCN2CCOCC2)cc1

Procedure:
A stirred mixture of 10.0 g (0.0119 mole) of 4,4'-((4-chloro-1,3-phenylene)bis(sulfonyl-3,1-propanediyl))bismorpholine bis(4-methylbenzenesulfonate), 1.6 g (0.012 mole) of 90% p-thiocresol and 1.5 g (0.038 mole) of sodium hydroxide in 55 ml of water was warmed for 30 minutes at 65° to 70° C., during which time the crude product separated as a hard gum. The aqueous phase was decanted, and the gum was dissolved in a minimum of warm propanol-2. This solution was treated with a propanol-2 solution of an excess of p-toluenesulfonic acid monohydrate. On cooling, the solution yielded a crystalline product. Recrystallization from propanol-2 gave the pure product, 4,4'-((4-((4-methylphenyl)thio)-1,3-phenylene)bis(sulfonyl-3,1-propanediyl))bismorpholine bis(4-methylbenzenesulfonate), as buff crystals, m.p. 215.5°-216.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22].N>C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:26])=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)N=C=O
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: C
Agent: N
Product: CC(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared from 0.5 g of 6-(2,6-dichlorophenyl)-pyrido{2,3-d]pyrimidine-2,7-diamine from Example 1 and 0.172 mL of isopropyl isocyanate according to Example 2. The product was purified by MPLC eluting with a gradient of CHCl3 :EtOAc (1:1) to afford the pure product; mp 184°-188° C., CIMS (1% ammonia in methane): m/z (relative intensity) 391 (MH+, 16), 393 (MH+ +2, 11), 306 (100).