Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.[CH2:41](Cl)Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:41][N:32]1[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[O:40]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 0 °C

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester (4.9 g) was dissolved in 200 mL dry DCM and stirred on 0° C. bath. 100 mL 4N HCL in dioxane was added and the mixture stirred to rt over 3 h. The solvents were evaporated and the residue was evaporated from diethyl ether 4 times. 4 g of the residue was dissolved in 250 mL dry dioxane and 462 mg paraformaldehyde was added while stirring. Then 62.5 mL trifluoroacetic acid was added and the mixture was stirred 1.5 h. The solvents were then evaporated and the residue was dissolved in 250 mL EtOAc and 250 mL saturated aqueous NaHCO3, and 4.2 g di-t-butyl dicarbonate was added and stirred 18 h at rt. The layers were then separated and the organic layer was washed with brine, dried with Na2SO4, and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to give 3.25 g after drying under vacuum. 1H NMR (400 MHz, acetone-d6): 7.72 (d, 1H), 7.61 (d, 1H), 7.51-7.42 (m, 3H), 7.12-7.07 (m, 2H), 0.680-6.70 (m, 2H), 5.20 (s, 2H), 5.13-5.07 (m, 1H), 5.02 and 4.76 (m, 1H), 4.66-4.52 (dd, 1H), 4.42 (d, 1H), 4.36-4.30 (m, 1H), 4.01 (m, 1H), 3.64 and 3.60 (s, 3H), 3.18-3.00 (m, 2H), 1.49 and 1.43 (s, 9H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:19])([F:18])[C:8]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:9][CH2:10][CH2:11][OH:12].[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C1COCC1.C(OCC)C>[C:20]([O:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([F:15])([F:16])[F:17])([OH:13])[C:7]([F:18])([F:19])[F:6])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: OCCCC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCC(O)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a 3-necked, 2-L round-bottomed flask equipped with an overhead stirrer, digital thermometer and a 1-L constant-pressure addition funnel with a nitrogen inlet was added 590 mL (0.944 mol) of n-butyllithium (1.6 M in hexane). The addition funnel was charged with a solution of 107 g (0.47 mol) of 1,1,1-trifluoro-2-trifluoromethyl-2,5-pentanediol in 300 mL of anhydrous THF. The flask was cooled and the diol was added dropwise with stirring while maintaining a temperature below 15° C. The resulting yellow-orange solution was stirred for an additional 2 hours at which time a solution of 54.5 g (0.52 mol) of methacryloyl chloride in 200 mL of anhydrous THF was added dropwise over 1 h at 10° C. The reaction mixture was allowed to reach room temperature overnight after which it was diluted with 500 mL of diethylether and washed with 2×500 mL of saturated ammonium chloride and brine, dried over MgSO4, evaporated and distilled at 74° C. at 1.0 mm Hg (0.5 g of phenothiazine was added to the pot prior to distillation) to yield 109 g (79%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:10]1=[O:22].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.[F:63][C:64]([F:72])([F:71])[CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C(Cl)Cl>[Cl:23][C:6]1[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:68]3[CH2:69][CH2:70][CH:65]([C:64]([F:72])([F:71])[F:63])[CH2:66][CH2:67]3)=[O:31])=[CH:26][CH:25]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:10]1=[O:22]
Reactant: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1
Reactant: FC(F)(F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Mix 3′,5′-dichloro-4′-[(R)-trans-1-(4-methoxy-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.350 g, 0.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.216 g, 1.11 mmol), N-methylmorpholine (0.33 mL, 2.95 mmol), hydroxybenzotriazole (0.247 g, 0.74 mmol) and 4-trifluoromethyl-piperidine hydrochloride (0.226 g, 1.47 mmol) in CH2Cl2 (10 mL). Stir for 12 hours at room temperature. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate brine. Dry over magnesium sulfate, filter, and concentrate under vacuum. Purify by flash column chromatography to recover 0.350 g (78%) of the title compound: MS (m/z): 611 (M+).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:13]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].IC>O>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([O:9][CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3,5 difluoro-2-nitrophenol(8.3 g), N,N-dimethylformamide(30 mL), potassium carbonate(10 g) and iodomethane(5 mL) was stirred vigorously at room temperature for 18 h. The mixture was diluted with water and extracted with ether. The extract was washed with brine, dried and evaporated to dryness to give the product(8.7 g) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:11]1([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH3:2][O:3][N:4]=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=NOC)c1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
1.4 g (16.8 mmol) of O-methylhydroxylamine hydrochloride and 1.16 g (8.4 mmol) of potassium carbonate were added to a solution of 0.50 g (2.8 mmol) of ethyl phenylglyoxylate in N,N-dimethylformamide, and the resulting mixture was stirred at 90° C. for 4 hours. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel, eluted with a stepwise gradient of ethyl acetate (10-30%) in hexane, to give 0.47 g (67% yield) of the less polar isomer of the title compound and 0.13 g (19% yield) of the more polar isomer of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:30]([NH2:32])=[O:31])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)[CH:15]=4)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Br:39][CH2:40][CH2:41]Br.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Br:39][CH2:40][CH2:41][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[C:11]([C:30]([NH2:32])=[O:31])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)[CH:15]=4)=[CH:3][C:2]=1[Cl:1]
Reactant: BrCCBr
Reactant: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)cc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(OCCBr)c(Cl)c2)cc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.3 %

Procedure:
A 100 ml round bottom flask was loaded with 3-(3-chloro-4-hydroxyphenyl)-7-(1,1-dioxo-thiomorpholino)-9H-carbazole-1-carboxamide (49.4 mg, 0.084 mmol, Example 408B), K2CO3 (150 mg, 1.085 mmol), DMF (6 ml) and 1,2-dibromoethane (0.09 ml, 1.044 mmol) and stirred at room temperature for 4.5 hours. The reaction mixture was poured into a separating funnel that was loaded with 100 ml water+citric acid (0.5 M solution in water) (10 ml, 5.00 mmol) and extracted with ethyl acetate. The organic layer was washed with dilute (1+5) aq. NaHCO3 solution, then brine, dried over MgSO4, filtered and evaporated to dryness to give 48.6 mg 3-(4-(2-bromoethoxy)-3-chlorophenyl)-7-(1,1-dioxo-thiomorpholino)-9H-carbazole-1-carboxamide, which was used without further purification. Estimated purity (from LCMS) ˜90%. MS (ESI) m/e+=576/578/580, m/e−=574/576/578 consistent with isotope pattern for 1 Br and 1 Cl.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[NH2:20][CH2:21][CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1>COCCO>[NH:25]1[CH:24]=[C:23]([CH2:22][CH2:21][NH:20][C:2]2[NH:3][C:4](=[O:19])[C:5]3[N:6]=[CH:7][N:8]([C:17]=3[N:18]=2)[C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)[N:27]=[CH:26]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)nc(Cl)nc32)C[C@@H]1O
Reactant: NCCc1c[nH]cn1
Solvent: COCCO
Product: O=c1[nH]c(NCCc2c[nH]cn2)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 0 °C

Procedure:
A mixture of 2-chloro-2′-deoxyinosine (6.0 g, 20.97 mmol) and histamine (4.4 g, 40 mmol) in 2-methoxyethanol (60 ml) was heated in a steel bomb at 110° C. for 12 hrs. The bomb was cooled to 0° C., opened carefully and the precipitated solid was filtered. The solid was washed with methanol and acetone and crystallized from DMF/water to give 6 g (79%) of pure 125. mp 220-222° C.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][N:7]=1.[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3]1[S:4][C:5]([CH2:8][NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:6][N:7]=1
Reactant: Nc1nccs1
Reactant: CN(c1ncc(C=O)s1)C1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(c1ncc(CNc2nccs2)s1)C1CCCCO1
Yield: 14.6 %

Procedure:
A solution of 2-(methyl(tetrahydro-2H-pyran-2-yl)amino)thiazole-5-carbaldehyde (250 mg, 1.10 mmol) and 2-aminothiazole (110 mg, 1.10 mmol) in toluene (11 mL) and molecular sieves 3 Å were stirred at reflux overnight. The strongly yellow solution of the corresponding imine was then poured over NaBH4 (212 mg, 5.61 mmol) in hot EtOH (80 mL). The colorless solution was filtered, concentrated and purified by column chromatography yielding N-methyl-N-(tetrahydro-2H-pyran-2-yl)-5-((thiazol-2-ylamino)methyl)thiazol-2-amine (50 mg, 17%) as a solid.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1)([O-:3])=[O:2].[NH3:16]>[Cl-].C([N+](CC)(CC)CC)C.O>[NH2:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([Cl:10])=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(F)(F)F)c1Cl
Reactant: N
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 10 h

Procedure:
260 g of 3-nitro-2,5-dichlorobenzotrifluoride, 130 ml of water and 10 g of tetraethylammonium chloride were introduced into an autoclave, and 120 ml of liquid ammonia were injected. The mixture was then heated to 130° C. and stirred for 10 hours at this temperature. After cooling, the batch was filtered and the precipitate which had been separated off was washed with water and dried. 194 g of 2-amino-3-nitro-5-chloro-benzotrifluoride with a melting point of 67° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([OH:26])=O)[C:13]2=[O:27])=[O:10])[CH:5]=[C:4]([Cl:28])[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN1C(=O)CCC1>[Cl:28][C:4]1[CH:5]=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)=[O:26])[C:13]2=[O:27])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)nc(Cl)c2)c1=O
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCN(C(=O)Cn2c(=O)c3ccccc3n(CC(=O)Nc3cc(Cl)nc(Cl)c3)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of {1-[(2,6-dichloro-pyridin-4-ylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (13.5 mg, 0.0318 mmol) in dry NMP (1.5 ml), HATU (13.3 mg, 0.035 mmol) is added followed by triethylamine (4.89 μL, 0.035 mmol). The orange solution is stirred at RT for 10 minutes, then treated with 1-methyl piperazine (3.89 μL, 0.035 mmol). The reaction mixture is stirred at RT and monitored by HPLC/LCMS until the starting material is consumed. The reaction mixture is partitioned between EtOAc (5 ml) and water (5 ml). The organic layer is separated and washed with brine (5 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by passing down a 5 g Isolute™ SCX2 (solid-supported sulfonic acid resin) cartridge, eluting with DCM (20 ml), MeOH (20 ml), and 7N NH3 in MeOH. The basic ammonia wash is concentrated in vacuo to afford the title compound as a white solid, [M+H]+ 505.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:27]1N=C(N2CCC(F)(F)C2)[C:30]2N=[N:34][NH:33][C:31]=2[N:32]=1)(C)(C)C.ClCC1N(C)C(C)=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:32]([CH3:27])[C:31]([CH3:30])=[N:33][N:34]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cc1nnc(CCl)n1C
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole and isolated as light yellow solid. MS (m/e): 392.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:18]=[CH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.ClCCl.[I-].C(OC([N:40]1[CH2:43][CH:42]([Zn+])[CH2:41]1)=O)(C)(C)C.Cl>CN(C)C(=O)C.[Cu]I>[NH:40]1[CH2:43][CH:42]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:18]=[CH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:28]=2)[CH2:41]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Agent: [Cu]I
Agent: Cl
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-(2,4-difluorophenyl)-1H-1,2,4-triazole (300 mg, 0.6 mmol) was dissolved in N,N-dimethyacetamide and purged with nitrogen. Added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.04 mmol) and copper(I) iodide (10 mg, 0.08 mmol). Bubbled in nitrogen for 10 minutes. Added (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (230 mg, 0.65 mmol) in 2.3 mL DMA. Heated at 80° C. overnight. Complete reaction was confirmed by LCMS. Diluted reaction mixture with 1 M HCl and extracted the t-Boc protected intermediate, tert-butyl 3-(2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)azetidine-1-carboxylate, with ethyl acetate. Dried over magnesium sulfate and concentrated in vacuo. Purified by flash chromatography (0 to 50% ethyl acetate in hexanes). Concentrated in vacuo and re-dissolved the residue in 10 mL 1,4-dioxane. Added 5 mL 4 N HCl in dioxane and let stir for 2 hours. Complete deprotection was confirmed by LCMS. Concentrated in vacuo purified by HPLC to give 419 (21.1 mg, 7% yield, M=1 437.1).
Reaction SMILES: O[CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.Cl.[CH3:13][N:14](CC1NC2C(N=1)=NC=CC=2)[CH3:15]>>[CH3:13][N:14]([CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2)[CH3:15]
Reactant: OCc1cc2ncccc2[nH]1
Reactant: CN(C)Cc1nc2ncccc2[nH]1
Agent: Cl
Product: CN(C)Cc1cc2ncccc2[nH]1

Procedure:
2-Dimethylaminomethyl-4-azaindole is synthesized from 2-hydroxymethyl-4-azaindole by a procedure analogous to that described for the synthesis of 2-dimethylaminomethyl-1H-imidazo[4,5-b]pyridine monohydrochloride in the J. Het. Chem., 6, 759-760 (1969).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:26]([Mg]Br)[CH3:27]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (128.4 mg, 0.341 mmol) in tetrahydrofuran (4.0 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.17 mL, 0.512 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (122.5 mg, 0.301 mmol, 88%).
Reaction SMILES: [CH3:1][C:2]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[CH:20]([Si:22]([O:27][CH3:28])([O:25][CH3:26])[O:23][CH3:24])=[CH2:21]>C1(C)C=CC=CC=1>[CH3:13][C:2]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:6]=1[CH2:21][CH2:20][Si:22]([O:27][CH3:28])([O:25][CH3:26])[O:23][CH3:24])=[O:4]
Reactant: C=C[Si](OC)(OC)OC
Reactant: CSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1
Solvent: Cc1ccccc1
Product: CO[Si](CCc1cc(SC)ccc1C(=O)C(C)(C)N1CCOCC1)(OC)OC
Reaction time: 8 h
Yield: 54.7 %

Procedure:
11.18 g (40 mmol) of 2-methyl-1-(4-methylthiophenyl)-2-morpholino-1-propanone, 735 mg (0.8 mmol) of RuH2 (CO)(PPh3)3 and 7.3 ml (48 mmol) of vinyltr 60 ml of anhydrous toluene were degased with argon for 1/2 hour and boiled at reflux for 5 hours. After standing overnight, boiling was repeated for 4 hours, then 360 mg (0.4 mmol) of RuH2 (CO)(PPh3)3 and 2 ml (13 mmol) of vinyltrimethoxysilane were added, and the mixture was stirred at reflux for a further 5 hours. Concentration and chromatography (silica gel, CH2Cl2 /ethyl acetate) gave 3.04 g (18%) of a yellowish oil. 1H-NMR (CDCl3): 1.01 ppm (2H, mc, Et-H2); 1.22 ppm (6H, s, Pr-H3, CH3); 2.50 ppm (3H, s, -SCH3); 2.58 ppm (4H, mc, *morpholine--O--CH2); 2.69 ppm (2H, mc, Et-H1); 3.59 ppm (9H, s, Si(OCH3)3); 3.70 ppm (4H, mc, **morpholine--N--CH2); 7.03 ppm (1H, dd, Ph-H5, 3 JH5, H6 =8.4 Hz, 4JH3,h5 =2.0 Hz); 7.11 ppm (1H, d, Ph-H3); 8.47 ppm (1H, d, Ph-H6).
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([NH:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.CCN(C(C)C)C(C)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[N:33]1>C(Cl)Cl>[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37]([NH:1][C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][C:4]([NH:12][C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=5)=[O:14])([CH2:5]4)[CH2:3]2)[CH2:9]3)=[O:38])=[N:33]1
Reactant: Cn1ccc(C(=O)Cl)n1
Reactant: Cc1cccc(C(=O)NC23CC4CC(CC(N)(C4)C2)C3)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)NC23CC4CC(C2)CC(NC(=O)c2ccn(C)n2)(C4)C3)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To a solution of 6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide (Intermediate 1, 20 mg, 0.07 mmol) in DCM (5 mL) was added DIEA (30 mg, 0.2 mmol) and 1-methyl-1H-pyrazole-3-carbonyl chloride (20 mg, 0.1 mmol, Maybridge Chemical Co., Cornwall, UK). After stirring at room temperature for 16 h, the reaction mixture was partitioned into dichloromethane and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a RP-HPLC/MS purification system (Gradient: acetonitrile in water, 25-95%, in 3.9 minutes with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium formate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)) to afford 10 mg (30%) of the title compound, 6-methyl-pyridine-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide, as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, br, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.26-7.21 (m, 1H), 6.76-6.72 (m, 2H), 3.89 (s, 3H), 2.55 (s, 3H), 2.54-2.52 (m, 2H), 2.35-2.08 (m, 10H), 1.72-1.69 (m, 2H). ESI-MS m/z: 394.1 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:3][CH2:2]1.[NH:23]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:24]1.O>ClCCl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:26][CH2:27][N:23]([C:11]([N:4]3[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[O:1][CH2:2][CH2:3]3)=[O:13])[CH2:24]2)[CH:29]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCOc2ccccc21
Reactant: c1cncc(C2CCNC2)c1
Solvent: O
Solvent: ClCCl
Product: O=C(N1CCC(c2cccnc2)C1)N1CCOc2ccccc21
Temperature: 100 °C
Yield: 92.2 %

Procedure:
0.2 g of 4-nitrophenyl 2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate, 0.1 g of 3-(pyrrolidin-3-yl)pyridine and 1.5 ml of water are introduced into a 10 ml glass tube. The tube is sealed and then heated at 100° C. under microwave irradiation for 35 minutes. Dichloromethane is added. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol gradient from 1/0 to 95/5. 0.19 g of 4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazine is obtained.