Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([CH3:14])=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.CO.C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[S:30])[NH:8][C:7]([CH3:14])=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(=O)[nH]c(C)c(-c3ccccc3)c2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2c(=S)[nH]c(C)c(-c3ccccc3)c2c1
Yield: 148.2 %

Procedure:
A mixture of 6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one (0.7 g) and Lawesson's reagent (1.3 g) in 7 mL toluene was heated to reflux for 12 h. After cooling, the reaction was subjected directly to flash chromatography (5% MeOH/CH2Cl2) to give a solid, which was triturated with diethyl ether to provide 1.1 g of 6-methoxy-3-methyl-4-phenylisoquinoline-1(2H)-thione.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])([F:31])[F:30])=[CH:4][CH:3]=1.I[C:34]1SC2C(C)=CC=C(C(F)(F)F)C=2N=1>>[CH3:34][C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])([F:30])[F:31])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(F)(F)F)c2nc(I)sc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Product: Cc1ccc(C(F)(F)F)c2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc12

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-7-methyl-4-trifluoromethyl-1,3-benzothiazole and conducting the Suzuki coupling at 55° C. for 3 h, the title compound was obtained as a yellow-green solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 2.70 (s, 3H), 3.07-3.18 (m, 2H), 3.37-3.44 (m, 2H), 3.54 (brs, 2H), 4.47-4.56 (m, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 8.08 (d, J=0.8 Hz, 1H), 8.41-8.46 (m, 2H), 8.57 (d, J=2.4 Hz, 1H), 8.76 (brs, 1H), 8.96 (brs, 1H), MS(ES+): m/z=459.09 (100) [MH+]. HPLC: tR=2.32 min (ZQ3, polar—5 min).
Reaction SMILES: C[CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:12][C:4]=2[O:3]1.CC1(C)C(=O)NC2C=CC(C(=O)CC)=CC=2O1>>[O:16]=[C:13]([C:11]1[CH:10]=[CH:9][C:5]2[NH:6][C:7](=[O:8])[CH2:2][O:3][C:4]=2[CH:12]=1)[CH2:14][CH3:15]
Reactant: CCC(=O)c1ccc2c(c1)OC(C)C(=O)N2
Agent: CCC(=O)c1ccc2c(c1)OC(C)(C)C(=O)N2
Product: CCC(=O)c1ccc2c(c1)OCC(=O)N2

Procedure:
The following compounds were made by the above procedure, using the appropriate starting materials: 3,4-dihydro-2-methyl-7-(1-oxopropyl)-3-oxo-1,4(2H)-benzoxazine, mp 179°-179.5° C.; and 3,4-dihydro-2,2-dimethyl-7-(1-oxopropyl)-3-oxo-1,4(2H)-benzoxazine, mp 153°-155° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.[OH-].[Na+]>C1COCC1>[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][S:10]([C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=4)(=[O:11])=[O:12])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc([N+](=O)[O-])cc4)cc23)CC1
Yield: 99.1 %

Procedure:
By a method similar to Example 31, using 4-nitrobenzenesulfonyl chloride (997 mg, 4.05 mmol) was added to a mixture of 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (777 mg, 3.4 mmol) in 0.2 N sodium hydroxide (18.6 mL, 3.7 mmol) and THF (20 mL) gave 1.4 g of an orange foam. The product was crystallized from ethyl acetate/hexanes to give 485 mg (35%) of an orange powder. The mother liquors were purified by flash chromatography (silica gel, 5%,7% 2M ammonia in methanol/methylene chloride) to give 800 mg (57%) of the title compound as yellow foam: Total yield was 92%: mp=171-172° C.; MS(m/e): 416 (M+1), 414 (M−1); Calculated for C20H21N3O5S: C, 57.82; H, 5.09; N, 10.11. Found: C, 57.35; H, 4.96; N, 9.88.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.[O-]S([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=[CH:18][N+:19]=1[O-:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cccnc1-c1ccc(F)cc1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc[n+]([O-])c1-c1ccc(F)cc1F
Temperature: 30 °C

Procedure:
To a nitrogen purged, 12 L, 5-necked flask, fitted with an overhead stirrer, a thermocouple and a condenser, was charged ethyl 2-(2,4-difluorophenyl)nicotinate, 3 (144 g, 548 mmoles, 1.0 eq), and 4 L of CH2Cl2. With stirring, mCPBA was added over 5 minutes, and the temperature was gradually increased from 22 to 38° C. in 45 minutes (completeness of reaction determined by HPLC). The reaction was cooled to room temperature and the contents slowly poured into 3 L of water. Na2SO3 was added slowly (exotherm from 20 to 33° C.) until the peroxide test (starch/I2 paper) indicated no peroxides remained in the mixture. The aqueous layer was separated and the organic layer was washed with saturated NaHCO3 (˜3 L). The organic layer was dried with MgSO4, filtered, and concentrated to a brown thick oil. The oil was then treated with MTBE (2 L) and stirred to give a white precipitate, which was collected by filtration, washed with MTBE and dried under vacuum to give the title Compound 4.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:12])[C:10]=2[N:11]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>O1CCOCC1.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>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][NH:8][C:9](=[O:12])[C:10]=3[N:11]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=c1[nH]cnc2ccc(Cl)nc12
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: [K+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cnc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of 6-chloro-pyrido[3,2-d]pyrimidin-4(3H)one (1.0 g, 5.5 mmol) in dioxane (80 ml) and water (20 ml) was added 4-fluorophenylboronic acid (770 mg, 5.5 mmol), K2CO3 (2.28 g, 16.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (290 mg, 0.25 mmol). The mixture was heated at reflux for 20 hours. After cooling to room temperature, the reaction mixture was neutralized to pH 5-6 with acetic acid, concentrated to a small volume, filtered and washed with water to yield a crude product. The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 1:30, yielding the title compound as a white solid (1.2 g, yield: 90%) which was characterised by its mass spectrum as follows: MS (m/z): 242 ([M+H]+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)#[N:2].CN([C:17]([O:21][N:22]1N=NC2C=CC=N[C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CONC>C(Cl)Cl.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:22]([O:21][CH3:17])[CH3:23])=[O:8])#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(C(=O)O)cc1C#N
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)OC)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
To a stirred solution of 3-cyano-4-methoxybenzoic acid (1.0 g, 5.60 mmol) in DCM (30 mL) were added HATU (3.20 g, 8.01 mmol), N-methoxy,N-methylamine (0.82 g, 8.01 mmol) and TEA (2.3 mL, 17.01 mmol) at RT under a nitrogen atomosphere. The reaction mixture was then stirred at RT for 2 h, diluted with water and the aqueous layer was extracted with DCM (3×50 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 3-cyano-N,4-dimethoxy-N-methylbenzamide (1.3 g, 100%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH:19]([CH2:18][N:17]([C:28]([C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[C:22]5[S:21][CH:25]=[CH:24][CH:23]=5)=[O:29])[CH2:16]4)[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C27H24N4OS, 452.58; m/z found, 453.2 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.[CH3:25][C:26]1[CH:31]=[C:30]([N:32]([CH3:44])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH3:45])[C:27]=1[NH2:46]>CN(C)C=O.[Cl-].[Na+].O>[NH2:8][C@@H:9]([CH:10]([CH3:12])[CH3:11])[C:13]([NH:46][C:27]1[C:26]([CH3:25])=[CH:31][C:30]([N:32]([CH3:44])[CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:38][CH:39]=2)=[CH:29][C:28]=1[CH3:45])=[O:14]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cc(N(C)Cc2ccc(C(F)(F)F)cc2)cc(C)c1N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(N(C)Cc2ccc(C(F)(F)F)cc2)cc(C)c1NC(=O)[C@@H](N)C(C)C
Reaction time: 2 h

Procedure:
Tert-butyloxycarbonyl-L-valine (21.7 mg), N,N-diisopropyl-ethylamine (35 uL), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (0.38 g) and 2,6,N′-trimethyl-N′-(4-trifluoromethyl-benzyl)-benzene-1,4-diamine (15.4 mg) were mixed in dry N,N-dimethylformamide (0.2 mL) and stirred under argon for 2 hours. Brine (2 mL) was added and the reaction mixture was extracted with ethyl acetate (2×2 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography. 15.4 mg (61% yield) of the N-Boc-protected title compound was isolated and it was dissolved in trifluoroacetic acid/dichloromethane (1:1, 2 mL) and stirred at 25° C. for 30 minutes. The reaction mixture was concentrated in vacuo to furnish 18 mg (96% yield) of the title compound. LC-MS-TOF (m/z) 408 (MH+); tR=2.19, (UV, ELSD) 93%, 98%.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:27]([O:30][C:31]1[C:36]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:35][C:34]([CH3:41])=[CH:33][C:32]=1[SiH:42]([CH2:49]Cl)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:28]=[CH2:29].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1(C)C=CC=CC=1.CCCCCC>[CH2:27]([O:30][C:31]1[C:36]([C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:35][C:34]([CH3:41])=[CH:33][C:32]=1[SiH:42]([CH2:49][CH:8]1[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=2)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH:28]=[CH2:29]
Reactant: C=CCOc1c([SiH](CCl)c2ccccc2)cc(C)cc1C(C)(C)C
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCOc1c([SiH](CC2c3cc(C(C)(C)C)ccc3-c3ccc(C(C)(C)C)cc32)c2ccccc2)cc(C)cc1C(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
There was dissolved 3.51 g (12.61 mmol) of 2,7-di-tert-butylfluorene in 79 mL of THF, and the obtained solution was cooled down to −78° C. To the solution, 8.19 mL of a 1.54 M-concentration hexane solution of n-butyllithium was added slowly, 8.19 mL of said hexane solution containing 12.61 mmol of n-butyllithium. Temperature of the resultant mixture was raised up to a room temperature, and the mixture was stirred for 3 hours at a room temperature. The mixture was cooled down to −78° C., and a solution of 4.53 g (12.61 mmol) of (2-allyloxy-3-tert-butyl-5-methyl phenyl)chloromethylphenylsilane in 16 mL of toluene was added to the mixture. Temperature of the resultant mixture was raised up to a room temperature, and the mixture was stirred for 3.5 hours, thereby obtaining a reaction solution. A mixture of 35 mL of a 10% aqueous solution of sodium hydrogen carbonate and 35 mL of a 10% aqueous solution of sodium carbonate was added to the reaction solution at 0° C. To the obtained mixture, 41 mL of toluene was added, and the mixture was separated to the toluene solution and the aqueous solution. The toluene solution was dried over sodium sulfate, and the mixture was filtered. The obtained filtrate was concentrated under a reduced pressure, thereby obtaining quantitatively (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,7-di-tert-butyl fluoren-9-yl)methylphenylsilane.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]#[N:25])[CH:19]=[C:20]([CH3:22])[CH:21]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([C:2]2[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=2)[C:24]#[N:25])[CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Reactant: Cc1cc(Cl)cc(CC#N)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(Cl)c2)n1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a stirred mixture of 4-Chloro-5-isopropyl-2,6-dimethoxy-pyrimidine (23.8 g, 0.11 mol) and (3-Chloro-5-methyl-phenyl)-acetonitrile (47) (16.6 g, 0.1 mol) in anhydrous DMF (200 ml) in an ice-water bath under an atmosphere of nitrogen, was portionwise added 60% sodium hydride (8.8 g, 0.22 mol). After stirring for 1 hr, the mixture was stirred at room temperature for overnight. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and purified by silica gel column chromatography (eluent, EA:hexane (1:10)) to afford 24 g (69%) of a white solid. m.p. 105-106° C.; 1H NMR (200 MHz, CDCl3) δ: 1.11 (3H, d, J=7.1 Hz), 1.15 (3H, d, J=7.1 Hz), 2.32 (3H, s), 3.00 (1H, m), 4.00 (3H, s), 4.02 (3H, s), 5.33 (1H, s), 7.10-7.16 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[C:18]#[N:19])[N:5]=2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][CH2:35][C:36]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:29])[CH3:30])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[C:18]#[N:19])[N:5]=2)=[O:37]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc4nc(N)sc4n3)c2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc4nc(NC(=O)CCl)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-cyanophenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.330 mmol) produced in Example C43(vi) in N,N-dimethylformamide (3.0 mL) was added chloroacetyl chloride (42 μL, 0.528 mmol), and the mixture was stirred at room temperature for 4 hr. Chloroacetyl chloride (21 μL, 0.264 mmol) was further added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-cyanophenyl]-3-(1-cyano-1-methylethyl)benzamide as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH2:32][C@H:33]([C:42]([O:44][CH3:45])=[O:43])[CH2:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[C@H:33]([CH2:34][C:35]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:41])[NH:32][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][CH:19]=2)[CH:11]=1
Reactant: COC(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(C(=O)Nc2cccc(C(=O)O)c2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(NC(=O)c2ccc(C#N)cc2)c1
Yield: 65 %

Procedure:
m-(p-Cyanobenzamido)benzoic acid is activated in the same manner as described under a) and coupled with the p-toluenesulphonate of H-Asp(OtBu)OMe in DMF at room temperature. There is isolated 3-(t-butoxycarbonyl)-N-[m-(p-cyanobenzamido)benzoyl]-L-alanine methyl ester in the form of colourless crystals. Yield: 65%, m.p. 83°-84° C. (hexane).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:17])[C:5]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:9][C:6]=2[O:7][CH:8]=1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O>C(O)(=O)C>[CH:2]([C:3]1[C:4](=[O:17])[C:5]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:9][C:6]=2[O:7][CH:8]=1)=[O:1]
Reactant: O=c1c(CO)coc2cc3c(cc12)CCCC3
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1coc2cc3c(cc2c1=O)CCCC3
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.3 g (0.01 mole) of 3-(hydroxymethyl)-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-4-one and 15 ml of glacial acetic acid is added to a solution of 2.98 g (0.01 mole) of sodium dichromate dihydrate in 15 ml of glacial acetic acid, keeping the temperature at about 50°C. with mild cooling. After 15 minutes, the reaction is heated at 60°C. for 15 minutes, water (100 ml) is added and the mixture is heated at 50°C. for 5 minutes. The separated solid is filtered, washed with water and dried; wt. 1.6 g (70%); mp 120°-123°C. Purification is effected by dissolving in methylene chloride and filtering through a layer of silica gel. The pure aldehyde is obtained by removal of solvent from the filtrate; mp 128°-130°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]2[CH2:17][CH2:16][C:15]3([CH3:18])[C:13]2([C:19](O)=[O:20])[CH2:14]3)[N:4]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.[NH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]>ClCCl>[CH3:39][O:38][C:36]([CH2:35][NH:34][C:19]([C:13]12[CH2:14][C:15]1([CH3:18])[CH2:16][CH2:17][CH:12]2[O:11][C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=1)=[O:20])=[O:37]
Reactant: COc1cc(OC)nc(OC2CCC3(C)CC23C(=O)O)n1
Reactant: COC(=O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CNC(=O)C12CC1(C)CCC2Oc1nc(OC)cc(OC)n1
Reaction time: 0.08 h

Procedure:
1 g (3.4 mmol) of 2-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-5-methyl-bicyclo[3.1.0]hexane-1-carboxylic acid is dissolved in 50 ml of dichloromethane and mixed with 2.1 g of triethylamine. 0.53 g (3.4 mmol) of phosphorus oxychloride, dissolved in 5 ml of dichloromethane, is added dropwise at -5° C. and the mixture is subsequently stirred for 5 minutes. A solution of 0.9 g (7.1 mmol) of methyl aminoacetate (glycine methyl ester) in 5 ml of dichloromethane is then added, with continued stirring, to the solution of the acid chloride. The reaction mixture is then allowed to reach room temperature within the space of 15 minutes. Subsequently, the organic phase is separated off, washed three times with water, dried over magnesium sulphate and evaporated. The remaining residue is purified by means of (flash) chromatography. 2-(4,6-Dimethoxy-pyrimidin-2-yl-oxy)-5-methyl-bicyclo-[3.1.0]hexane-1-carboxylic acid N-(methoxycarbonyl-methyl)-amide is obtained in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([NH:15][S:16]([C:19]1[C:31]([CH3:32])=[CH:30][C:22]([O:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][C:20]=1[CH3:33])(=[O:18])=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CC(C)(C)C(Cl)=O.Cl.[NH2:49][CH2:50][CH2:51][NH:52][C:53](=[O:62])[O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([NH:15][S:16]([C:19]1[C:31]([CH3:32])=[CH:30][C:22]([O:23][CH2:24][CH2:25][CH2:26][C:27](=[O:28])[NH:49][CH2:50][CH2:51][NH:52][C:53]([O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:62])=[CH:21][C:20]=1[CH3:33])(=[O:18])=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)NS(=O)(=O)c1c(C)cc(OCCCC(=O)O)cc1C
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCNC(=O)OCc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the crude phenoxybutanoic acid (20) from the previous reaction (2.75 g) in CH2Cl2 (150 mL) cooled in an ice water bath was added 4-methylmorpholine (0.89 g, 8.8 mmol) and then trimethylacetyl chloride (1.06 g, 8.8 mmol). The reaction mixture was allowed to warm to rt. After 1 h, the reaction mixture was concentrated in vacuo then DMF (100 mL) was added and this was also removed in vacuo (to remove any unreacted trimethylacetyl chloride, bp 105-106° C.). The crude product was redissolved in CH2Cl2 (150 mL) and a solution of benzyl N-(2-aminoethyl)carbamate hydrochloride, 21 (1.52 g, 6.6 mmol) and 4-methylmorpholine (1.11 g, 11.0 mmol) in DMF was added. After 1 h, the reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. After separation of the layers, the EtOAc solution was washed with dilute NaHCO3 and water. The EtOAc solution was concentrated in vacuo to give the crude product. This material was purified by chromatography (97:3 EtOAc/MeOH) to give 2.80 g of product 22.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]([O-:11])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[Na+].C(Cl)(=O)C([Cl:16])=O>ClCCl.N1C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:9]([Cl:16])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1C(=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccnc1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.3 %

Procedure:
To a stirred suspension of sodium 3-methoxypyridine-2-carboxylate (Intermediate 94, ˜3.3 mmol) in dichloromethane (10 ml) and pyridine (5 ml) at 0 C (ice-bath) was added dropwise oxalyl chloride (0.58 ml, 6.6 mmol). The mixture was stirred 10 minutes, then DMF (1 drop) was added. The mixture was warmed to room temperature and stirred 2 h then concentrated under vacuum. The residue was dissolved in dichloromethane (10 ml) and filtered through a plug of cotton wool. The filtrate was concentrated under vacuum to give the title compound as a brown oil (0.16 g) which was used without further purification or characterisation.