Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)(C)(C)C.[ClH:23].O1CCOCC1>>[ClH:23].[ClH:23].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[C:17]([N:18]([CH3:20])[CH3:19])=[O:21]
Reactant: CN(C)C(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H](N)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-[2-(4-Amino-phenyl)-1-dimethylcarbamoyl-ethyl]-carbamic acid tert-butylester (214 mg, 0.7 mmol) was dissolved in 4M HCl-dioxane (2 mL) at 0° C. and the solution stirred for 2 hours at 25° C. The mixture was concentrated and the residue triturated with ether. Yield, 294 mg, 102%; PBMS 208 (MH+, 100%).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[CH2:6][CH2:5][NH:4]1.[H][H]>C(O)C>[ClH:1].[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5][NH:4]1
Reactant: CC1NCCc2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: Cl
Solvent: CCO
Product: CC1NCCc2ccc(N)cc21

Procedure:
A suspension of 1-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.0 g, 8.75 mmol) in ethanol (100 ml) and a catalytic quantity of 10% Pd--C was hydrogenated until no more hydrogen was taken up. The catalyst was filtered off, the solvent was concentrated to a small volume, ether was added and the precipitated solid was collected and dried: 1.39 g (78%), MS (M+H)+ 163.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]1[O:28][C:27]2[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][C:17]=2[O:16]1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][C:27]4[O:28][CH2:15][O:16][C:17]=4[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCO4)nc2n(CC)c1=O
Yield: 37.4 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.33 g (12.1 mmol) of 3,4-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 1.34 g (yield 38%) of Compound 78 as a yellowish green powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:39])[NH:33][CH2:34][CH:35]([OH:38])[CH2:36][NH2:37])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:37][CH2:36][CH:35]([OH:38])[CH2:34][NH:33][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:39])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(O)CNC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 300 mg (0.82 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 202 mg (1.06 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate in 6 ml of dimethylformamide with the addition of 204 mg (1.06 mmol) of EDC and 33 mg (0.25 mmol) of HOBt.
Reaction SMILES: C(O)C.F[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[N:6]=1.C(=O)(O)[O-].[Na+].[CH2:20]1[O:29][C:28]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=2[O:21]1>O>[F:14][C:7]1[N:6]=[C:5]([NH:25][C:24]2[CH:26]=[CH:27][C:28]3[O:29][CH2:20][O:21][C:22]=3[CH:23]=2)[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(F)nc1Nc1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
In 75 ml. of ethanol was dissolved 3.2 g. (0.002 mole) of 2,6-difluoro-3-nitropyridine followed by 1.68 g. (0.02 mole) of sodium bicarbonate. To this stirred mixture, was added a solution of 2.74 g. (0.02 mole) of 3,4-(methylenedioxy) aniline in 50 ml. of ethanol dropwise over 45 minutes at room temperature. After one hour, 100 ml. of water was added and the deep-red crystalline solid product was collected. A small amount was crystallized from ethanol and melted at 161°-162° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(CO)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 53(B)(a), 110 mg, 0.26 mmol) in diethyl ether (500 μL) was cooled to 0° C. and then slowly treated with lithium aluminum hydride (15 mg, 0.38 mmol). The reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. After 1 h at 25° C., thin layer chromatography still indicated the presence of the starting material. An additional amount of lithium aluminum hydride (10 mg, 0.26 mmol) was added to the reaction mixture, and the reaction mixture was allowed to stir at 25° C. for 1 h. The reaction mixture was then slowly quenched by the dropwise addition of water (10 mL). The resulting mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded the 3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide (60 mg, 57%) as a yellow foam: mp 74-77° C.; EI-HRMS m/e calcd for C21H26N2O4S (M+) 402.1613, found 402.1617.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:25]([C:2]1[N:3]=[C:4]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:26]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Cl)cc3ccccc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccccc23)C1
Yield: 83 %

Procedure:
A solution of (S)-tert-butyl 3-((3-chloroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (4.430 g, 12.70 mmol), zinc cyanide (2.980 g, 25.40 mmol) and Pd(PPh3)4 (1.468 g, 1.27 mmol) in DMF (36.3 mL) was heated at 160° C. for 20 minutes in a microwave reactor. The reaction mixture was filtered, diluted with water (400 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica column chromatography to give the title compound as a white-to-pale-yellow solid (3.570 g, 83%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=13.18 Hz, 9H), 2.23 (d, J=11.23 Hz, 2H), 3.42-3.59 (m, 3H), 3.65-3.75 (m, 1H), 5.68-5.80 (m, 1H), 7.82-7.89 (m, 1H), 7.91-7.98 (m, 1H), 8.06 (d, J=8.79 Hz, 1H), 8.21-8.30 (m, 2H); ESI-MS m/z [M+H-tert-butyl]+ 284.6.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)[C:3]=1[C:4]#[N:5].[CH3:17][N+:18]([CH3:20])=[CH2:19].[I-]>CN(C=O)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N:11]2[C:15]([CH2:17][N:18]([CH3:20])[CH3:19])=[C:14]([CH3:16])[N:13]=[CH:12]2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1cn(-c2ccc(F)c(Cl)c2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(F)c(Cl)c2C#N)c1CN(C)C
Yield: 52 %

Procedure:
In analogy to example 5b, 2-chloro-3-fluoro-6-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 16 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 97:3) afforded the title compound as a light yellow oil (yield: 52%). MS: m/e=293.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:24])[CH2:15][C@@H:14]([C@@H:25]([OH:36])[CH2:26][C@H:27]([C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])[NH:13][C:12](=[O:37])[C@H:11]([CH3:38])[NH:10][C:9]1=[O:39])(C)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>Cl.O1CCOCC1>[C:41]([NH:7][C@@H:8]1[C:9](=[O:39])[NH:10][C@@H:11]([CH3:38])[C:12](=[O:37])[NH:13][C@H:14]([C@@H:25]([OH:36])[CH2:26][C@@H:27]([CH3:28])[C:29]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:35])[CH2:15][C@H:16]([CH3:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]1C[C@H](C)CCCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]1C[C@H](C)CCCCCCC[C@H](NC(C)=O)C(=O)N[C@@H](C)C(=O)N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 45 mg (0.079 mmol) [(3S,6S,14R,16S)-16-((1S,3R)-3-butylcarbamoyl-1-hydroxy-butyl)-3,14-dimethyl-2,5-dioxo-1,4diaza-cyclohexadec-6-yl]-carbamic acid tert-butyl ester (example 6) in 1 ml 4N HCl/dioxane is kept for 3 h and then evaporated. The residue is taken up in 3 ml THF and 1 ml EtOH and 1 ml 10% aqueous sodium carbonate, cooled to 0° C. and stirred vigorously. 0.112 ml (1.6 mmol) acetyl chloride are added and stirring is continued for 1 h. The solvents are evaporated and the residue is stirred with water and TBME/hexane for 30 min. The mixture is filtered to yield the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Fc1ccc(SCCCBr)cc1
Reactant: CCCCc1nc2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2ccccc2n1C1CCN(CCCSc2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 87.8 %

Procedure:
To a stirred solution of 1-(3-bromopropylsulfanyl)-4-fluorobenzene (0.2 g) and 2-butyl-1-piperidin-4-yl-1H-benzimidazole (0.3 g) in DMF (5 ml) was added K2CO3 (0.6 g) and KI (0.05 g). The mixture was heated at 100° C. for 1 h, and then allowed to cool to rt. Water (50 ml) was added and the mixture extracted with ethyl acetate (80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The oil was purified by flash chromatography (9:1 DCM:MeOH) to yield 0.3 g of the title compound as colourless crystals. Mp. 159-161° C.
Reaction SMILES: [OH-].[K+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[SH:8].CS(O[CH:14]1[CH2:17][N:16]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1)(=O)=O>C1COCC1>[CH:18]([N:16]1[CH2:17][CH:14]([S:8][C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[CH2:15]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Sc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(C(c2ccccc2)N2CC(Sc3cccs3)C2)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Potassium hydroxide (141 mg, 2.52 mmol) and thiophene-2-thiol (292 mg, 238 μL) were added to a solution of 1-benzhydrylazetidin-3-yl methanesulfonate (400 mg, 1.26 mmol) solubilized in THF (7 mL). The reaction mixture was stirred a first time under microwave irradiations (100 W) at 80° C. for 30 minutes. Potassium hydroxide (141 mg, 2.52 mmol) and thiophene-2-thiol (292 mg, 238 μL) were added and the reaction mixture was stirred for a second time under microwave irradiations (100 W) at 80° C. for 30 minutes. After concentration to dryness, the residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (1:0 to 9:1) as eluent. The title product was obtained as a yellow solid (160 mg, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:34][C:35]3[N:39]([CH2:40][C:41](O)=[O:42])[C:38]4[CH:44]=[CH:45][C:46]([C:48]#[N:49])=[CH:47][C:37]=4[N:36]=3)[C:22](=[O:33])[C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:62]([O:69][C:70]1[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH2:34][C:35]3[N:39]([CH2:40][C:41](=[O:42])[NH:74][C:73]4[CH:72]=[CH:71][C:70]([O:69][CH2:62][C:63]5[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=5)=[CH:76][CH:75]=4)[C:38]4[CH:44]=[CH:45][C:46]([C:48]#[N:49])=[CH:47][C:37]=4[N:36]=3)[C:22](=[O:33])[C:23]3[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:28]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)N(Cc2nc3cc(C#N)ccc3n2CC(=O)O)c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)N(Cc2nc3cc(C#N)ccc3n2CC(=O)Nc2ccc(OCc3ccccc3)cc2)c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 75.3 %

Procedure:
2-[N-[4-(1-tert-Butoxycarbonylpiperidin-4-yloxy)phenyl]-N-(4-methoxycarbonylbenzoyl)aminomethyl]-5-cyanobenzimidazole-1-acetic acid (632 mg), 1-hydroxybenzotriazole hydrate (128 mg), 4-benzyloxyaniline hydrochloride (223 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (182 mg) and N-methylmorpholine (0.104 ml) were treated in the same manner as in Example 17, Step 10. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7-2:8) to give the title compound (605 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:22]=[CH:21][C:13]2[O:14][C:15]([CH3:20])([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=2[CH:11]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:22]=[CH:21][C:13]2[O:14][C:15]([CH3:19])([CH3:20])[C:16]([CH3:18])=[CH:17][C:12]=2[CH:11]=1
Reactant: COc1ccccc1Sc1ccc2c(c1)C=C(C)C(C)(C)O2
Agent: [I-]
Agent: [Li+]
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CC1=Cc2cc(Sc3ccccc3O)ccc2OC1(C)C
Temperature: 150 °C
Yield: 35.9 %

Procedure:
6-(2-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (3.5 g) (see Preparation 7) was dissolved in dry 2,4,6-collidine (15 ml), anhydrous lithium iodide (9.0 g) was added and the mixture was heated at 150° C for 40 hours. After cooling, the mixture was taken up in dichloromethane and washed with 2N aqueous hydrochloric acid solution (×3). The organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the residue was chromatographed on silica using 1:1 hexane:dichloromethane as the eluent to yield 6-(2-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (1.2 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=2[C:25]([NH:27][CH2:28][C:29]#[CH:30])=[O:26])[C:19]([Cl:35])=[CH:18][N:17]=1>>[Cl:35][C:19]1[C:20]([NH:22][C:23]2[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=2[C:25]([NH:27][CH2:28][C:29]#[CH:30])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: C#CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Product: C#CCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl

Procedure:
2-[5-Chloro-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-prop-2-ynyl-benzamide was prepared from 7-amino-1-methyl-1,3,4,5-tetrahydro-1-benzazepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a white solid (79 mg, 48%). m.p.=193-194° C.; LCMS (m/e) 475 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 10.97 (s, 1H), 8.66 (d, 1H, J=8.4 Hz), 8.14 (s, 1H), 7.57 (d, 1H, J=7.8 Hz), 7.54-7.42 (m, 3H), 7.19-7.09 (m, 2H), 6.95 (s, 1H), 6.34 (bs, 1H), 4.33-4.27 (m, 2H), 3.36 (s, 3H), 2.74-2.64 (m, 2H), 2.38-2.30 (m, 3H), 2.22-2.12 (m, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20].C(O)CO.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.[Cu]I>[F:22][C:13]([F:12])([F:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: FC(F)(F)c1ccccc1S
Reactant: Ic1cnc2ccccc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: FC(F)(F)c1ccccc1Sc1cnc2ccccc2c1
Yield: 112.9 %

Procedure:
A mixture of 3-iodoquinoline (6 g, 23.5 mmol), 2-trifluoromethyl benzenethiol (5 g, 28 mmol), CuI (225 mg, 3.89 mmol), ethylene glycol (3.5 g, 56.4 mmol), K2CO3 (8 g, 58 mmol) in isopropanol (20 mL) was refluxed under N2 for 12 h. The reaction mixture was filtered through a short pad of silica gel and the filtrate was concentrated in vacuo to dryness. The product was purified by flash column chromatography on silica gel to give the product 3-(2-trifluoromethyl-phenylsulfanyl)-quinoline (8.1 g, 95%)
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCc2ccccc2)ccc2c(O)noc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCc1c(OCc2ccccc2)ccc2c(OC)noc12

Procedure:
A solution of 3-hydroxy-6-benzyloxy-7-propyl benz[4,5]isoxazole (195 mg) in acetone (3 mL) was treated with methyl iodide (0.067 mL) and potassium carbonate (100 mg). The mixture was refluxed for 8 hours. The reaction was partitioned between isopropyl acetate and pH 4 buffer. The organic was dried over magnesium sulfate, filtered and concentrated to a solid, which was chromatographed over silica gel to afford the product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>N1C=CC=CC=1.N1CCCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 2 chloro-5-nitrobenzaldehyde (100 g., 0.54 mole), malonic acid (122 g., 1.2 mole) in pyridine (300 ml) and piperidine (5 ml) was heated at 100° C. for one hour, during which time considerable gassing occurred. After refluxing the reaction mixture for a further few minutes, it was then cooled. The resulting precipitate was collected, washed with water and dried to give an 80% yield, m.p. 226°-228° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:20]2[CH:21]=[C:22]3[C:28](I)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]3=[N:24][CH:25]=2)[CH:16]=[CH:17][C:18]=1[F:19])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]1[CH:39]=[C:40]([CH:58]=[C:59]([F:61])[CH:60]=1)[CH2:41][N:42]1[C:46]([CH3:47])=[C:45](B2OC(C)(C)C(C)(C)O2)[C:44]([CH3:57])=[N:43]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:20]2[CH:21]=[C:22]3[C:28]([C:45]4[C:44]([CH3:57])=[N:43][N:42]([CH2:41][C:40]5[CH:58]=[C:59]([F:61])[CH:60]=[C:38]([F:37])[CH:39]=5)[C:46]=4[CH3:47])=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]3=[N:24][CH:25]=2)[CH:16]=[CH:17][C:18]=1[F:19])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2cnc3c(c2)c(I)cn3C(=O)OC(C)(C)C)ccc1F)S(C)(=O)=O
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2ncc(-c3ccc(F)c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c3)cc12
Yield: 91.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-fluorophenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 66A)(85 mg, 0.134 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (93 mg, 0.269 mmol) using sodium carbonate (43 mg, 0.404 mmol) and Pd(PPh3)2Cl2 (5 mg, 0.006) in DME/water (20/4 mL) to afford 89 mg of the crude compound. MS: m/z=670.2 (M+1) (de boc mass observed).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>C(#N)C>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][NH:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CC#N
Product: COC(=O)CCNCCNC(=O)OC(C)(C)C
Yield: 52.1 %

Procedure:
Mono-BOC-ethylenediamine (2) (16.28 g, 0.102 mol) was dissolved in acetonitrile (400 mL) and methyl acrylate (91.5 mL, 1.02 mol) was transferred to the mixture with acetonitrile (200 mL). The solution was refluxed overnight under nitrogen in the dark to avoid polymerization of methyl acrylate. After evaporation to dryness in vacuo, a mixture of water and ether (200 mL+200 mL) was added, and the solution was filtered and vigorously stirred. The aqueous phase was extracted one additional time with ether and then freeze dried to yield a yellow solid. Recrystallization from ethyl acetate yielded 13.09 g (46%) of the title compound. M.p. 138°-140° C. Anal. for C11H23 N2O4Cl, found (calc.) C: 46.49 (46.72) H: 8.38 (8.20) N: 9.83 (9.91) Cl: 12.45 (12.54). 1H-NMR (90 MHz; DMSO-d6) δ: 1.39 (s, 9H); 2.9 (m, 8H); 3.64 (s, 3H).