Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:35])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=O.CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:1][C@@H:2]([CH3:35])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][Si:19]([CH:23]([CH3:24])[CH3:25])([CH:20]([CH3:21])[CH3:22])[CH:26]([CH3:28])[CH3:27])[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
N-[(2R)-2-hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxamide (48.7 g, 96.5 mmol) synthesized in Example (116b) was dissolved in tetrahydrofuran (600 mL), and anhydrous methanesulfonic acid (33.6 g, 193 mmol) and triethylamine (40.4 mL, 289 mmol) were added, followed by stirring at 50° C. for 3 hours under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (500 mL) was added, and extraction was carried out twice with ethyl acetate (500 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diisopropylether (300 mL) was added to the resulting residue, and the slurry was stirred to give a white solid, which was filtered off. Under reduced pressure, the solvent in the mother liquor was distilled off, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%). This was vacuum-dried together with the filtered product to afford the desired compound (34.8 g, yield 74%) as a white solid.
Reaction SMILES: C(OC([N:8]([C@@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37]C1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Cl:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: CN[C@@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Product: Cl

Procedure:
Intermediate 25b is used in the method of Example 39 instead of Intermediate 26 to obtain the title compound as hydrochloride.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])=[N:8][CH:9]=1.[CH3:17]I.O>CN(C)C=O.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH3:17])[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])=[N:8][CH:9]=1
Reactant: CN1CCC(c2ccc(Br)cn2)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(C)(c2ccc(Br)cn2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (55% in mineral oil, 0.17 g) was added to a solution of 3-(5-bromo-pyridin-2-yl)-1-methyl-pyrrolidin-2-one (0.77 g) and methyl iodide (0.44 mL) in N,N-dimethylformamide (15 mL) in argon atmosphere at room temperature. The resulting mixture was stirred at room temperature overnight. Water and ethyl acetate were then added and the organic phase of the resulting mixture was separated. The organic phase was washed with brine, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloro-methane/ethyl acetate 1:1) to give the title compound as a colorless oil. Yield: 0.50 g (61% of theory); LC (method 1): tR=1.60 min; Mass spectrum (ESI+): m/z=269/271 (Br) [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>C1COCC1.CO.CCOCC>[CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc(OC)nc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)c(C)c2)cn1
Reaction time: 12 h

Procedure:
To a solution of Methyl 2-methyl-4-(2-methoxypyridin-5-yl)-benzoate (600 mg, 2.6 mmol) (reference example 34a) in THF/MeOH (8 mL, 1/1) is added NaOH (3 mL, 1M). The resulting mixture is stirred for 12 hours then acidified with hydrochloric acid (2M, to give pH 5). The mixture is diluted with ether then washed with brine, dried over MgSO4 and concentrated. The residual solid is triturated with ether/hexane (1/20). The resulting product (500 mg) is used without further purification. 1H NMR (CDCl3) d 2.71 (s, 3H), 3.98 (s, 3H), 6.82 (d, J=8 Hz, 1H), 7.41 (m, 2H), 7.81 (dd, J=8, 2 Hz, 1H), 8.13 (d, J=8 Hz, 1H), 8.43 (d, J=2 Hz, 1H). MS (EI) m/z 243 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[N:15]=[C:14]1[C:9]([CH:10]=[CH:11][CH:12]=[C:13]1[C:17]([OH:19])=O)=[N:8]2.O.[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1.S(Cl)(Cl)=O>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[N:15]=[C:14]1[C:9]([CH:10]=[CH:11][CH:12]=[C:13]1[C:17]([NH:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1)=[O:19])=[N:8]2
Reactant: Nc1nnn[nH]1
Reactant: COc1cccc2nc3cccc(C(=O)O)c3nc12
Solvent: O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1cccc2nc3cccc(C(=O)Nc4nnn[nH]4)c3nc12
Temperature: 70 °C

Procedure:
To a stirred solution of 0.006 mole (1.5 g) of 9-methoxyphenazine-1-carboxylic acid and 0.006 mole (0.61 g) of 5-aminotetrazole monohydrate in 50 ml of pyridine was added dropwise 0.012 mole (1.4 g) of thionyl chloride. The mixture was warmed to 70° C., maintained at 70° C. for 20 minutes, then diluted with water. A solid product was separated from the mixture by filtration, washed with water and acetone, and dried. Recrystallization from N,N-dimethylformamide provided 9-methoxy-(N-tetrazol-5-yl)phenazine-1-carboxamide, in the form of orange needles, m.p. 325°-330° C. (dec.)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[NH:22][C:21](=[O:23])[CH2:20][CH2:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:29]([O:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([O:36][C:37]([NH:22][C@@H:18]([C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH2:19][CH2:20][CH2:21][OH:23])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CC[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (5R)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (12 g) in tetrahydrofuran (THF) (200 ml) were added butyllithium (26 ml, 1.6N solution in hexane) and benzyloxycarbonyl chloride (6.8 ml) at −78° C. under N2. The mixture was stirred for 1 hour at the same temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo, the residue was dissolved in THF (200 ml), and 1N-NaOH (87 ml) was added at 0° C. After being stirred for 12 hours at room temperature, the solvent was evaporated in vacuo. After the residue was partitioned between hexane and water, aqueous layer was adjusted to pH=2 and extracted with ethyl acetate. The organic layer was washed with water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was dissolved in THF (200 ml). To the solution were added triethylamine (9.0 ml) and ethyl chloroformate (5.0 ml) at −5° C. under N2 and the mixture was stirred for 1 hour at the same temperature. After the filtration, the solution was dropwise added to the solution of NaBH4 (3.2 g) in a mixture of THF (100 ml) and water (100 ml) at 0° C. and stirred for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R)-N-benzyloxycarbonyl-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (13 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2([CH2:36][C:37]([NH2:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:26]([Cl:40])=[CH:25][N:24]=1>>[Cl:40][C:26]1[C:27]([NH:29][C:30]2([CH2:36][C:37]([NH2:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Reactant: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(NC4(CC(N)=O)CCCCC4)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide in an analogous manner to Example 61e. Product isolated as a pale yellow foam (0.064 g, 49%). MP: 71-83° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 7.92 (s, 1H), 7.84 (s, 1H), 7.14 (s, 1H), 6.64 (s, 1H), 5.40 (br s, 1H), 5.24 (s, 1H), 5.05 (br s, 1H), 3.85 (s, 3H), 3.57-3.51 (m, 2H), 3.47-3.41 (m, 2H), 3.32 (s, 6H), 3.06-2.98 (m, 1H), 2.90 (s, 2H), 2.87-2.77 (m, 8H), 2.37-2.29 (m, 2H), 1.71-1.29 (m, 8H). MS: 561.29 (MH)+.
Reaction SMILES: [Cl:1][C:2]1([C:5]([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([CH2:14][CH2:15][C:16](O)=[O:17])=O)=[CH:10][CH:9]=2)=[O:6])[CH2:4][CH2:3]1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1([C:5]([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]3[CH2:14][CH2:15][C:16](=[O:17])[NH:22][N:23]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)C2(Cl)CC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(NC(=O)C3(Cl)CC3)cc2)=NN1
Yield: 92.1 %

Procedure:
2.75 g (9.3 millimoles) of 3-[p-(1-chlorocyclopropylcarbonylamino)-benzoyl]-propionic acid, 0.47 g (9.4 millimoles) of hydrazine hydrate and 20 ml of ethanol are refluxed for 6 hours. The product is filtered off at 10° C., washed with ethanol and dried under reduced pressure at 50° C., giving 2.5 g (92% of theory) of 6-[p-(1-chlorocyclopropylcarbonylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone as colorless crystals (identical with the compound from Example 7).
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(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC1C[S:46](=[O:49])(=[O:48])[CH2:45]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]([CH:14]3[CH2:45][S:46](=[O:49])(=[O:48])[CH2:15]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: O=S1(=O)CC(Br)C1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(C3CS(=O)(=O)C3)nc2n1

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-bromo-thietane 1,1-dioxide and isolated as white solid. MS (m/e): 387.3 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=O.C([BH3-])#[N:14].[Na+].C([O-])(=O)C.[NH4+]>CO>[CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[NH2:14]
Reactant: [BH3-]C#N
Reactant: CC(C)CC(=O)c1cccnn1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(N)c1cccnn1
Temperature: 70 °C
Yield: 27.1 %

Procedure:
A suspension of 3-methyl-1-(pyridazin-3-yl)butan-1-one (0.85 g, 5.2 mmol; CAN 138835-88-8), sodium cyanoborohydride (1.2 g, 19.2 mmol) and ammonium acetate (1.28 g, 16.6 mmol) in methanol (11.1 mL) was heated at 70° C. for 12 h. The solvent was removed under reduced pressure and the residual oil was partitioned between EtOAc and 1 M aqueous HCl solution. The aqueous layer was basified with 10% aqueous NaOH solution and extracted with EtOAc. The combined extracts were washed with brine and dried over Na2SO4. Filtration and evaporation provided the title compound (233 mg, 27%) as brown oil which was sufficiently pure to be used in the next reaction step. MS (EI): m/e=166.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[N+:18]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30])=[CH:10][CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:7]=2)([O-:20])=[O:19]
Reactant: NCCCN1CCCC1=O
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Product: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12
Yield: 88.1 %

Procedure:
4-Chloro-3-nitro-7-phenylquinoline (3.51 g, 12.3 mmol) was treated with 1-(3-aminopropyl)pyrrolidin-2-one (2.3 mL, 16 mmol) according to the method described in Part E of Example 1 to provide 4.23 g of 1-[3-(3-nitro-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one as a yellow solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:19][CH:18](OS(C)(=O)=O)[CH2:17]2)[S:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O-:28])(=[S:27])[CH3:26].[K+].C(OCC)(=O)C>CN(C)C=O>[C:25]([S:27][CH:18]1[CH2:17][N:16]([C:13]2[S:14][CH:15]=[C:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)[CH2:19]1)(=[O:28])[CH3:26]
Reactant: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
To a solution of 1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (739 mg, 2.01 mmol) (obtained as described in Reference Example 64(3)) in dimethylformamide (20 ml) was added potassium thioacetate (1.38 g, 12.1 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 3.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate=(1:1)→ethyl acetate as the eluant to afford 3-acetylthio-1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]azetidine (698 mg, yield 100%) as a pale brown solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.O>ClCCl>[CH3:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]([S:12]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:13])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1[N+](=O)[O-]
Reactant: CC(C)N
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(S(=O)(=O)NC(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of isopropylamine (13 mL, 155 mmol) in 60 mL of dichloromethane at 0° C. was added a solution of 5.3 g of 3-methyl-2-nitrobenzenesulfonyl chloride (prepared according to Courtin, A. Helv. Chim. Acta, 1976, 59, 379–387) in 60 mL of dichloromethane dropwise. The reaction mixture was stirred 2 hours at room temperature. Water was added and the layers were separated. The organic layer was dried (sodium sulfate) and the volatiles were removed with a rotary evaporator. The residue was purified by medium pressure liquid chromatography (MPLC), using 20–40% ethyl acetate in hexanes as eluant, to afford 4.3 g of the title compound as a yellow solid.
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH2:38])([CH3:37])[CH3:36])=[CH:30][C:29]=1[CH3:39].Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:38][C:35]([CH3:36])([CH3:37])[CH2:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([CH3:39])[CH:30]=2)[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(CC(C)(C)N)ccc1F
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Agent: Cl
Product: Cc1cc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)ccc1F

Procedure:
1.10 g (3.1 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.50 g (2.8 mmol) of 2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamine are reacted and worked up analogously to the method for Example 8(d). White solid. Yield: 0.75 g (47%, hydrochloride); melting point 228° C.–230° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C@H:18]1[CH2:23][N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20][N:19]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([N:31]([CH3:32])[C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:22]4[CH2:21][CH2:20][N:19]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C@@H:18]([CH3:17])[CH2:23]4)=[CH:30][CH:29]=3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=C(Cl)c1ccc(-c2cccc(F)c2)nc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(-c4cccc(F)c4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The acid chloride from step 1 was taken up in DCM and added drop-wise to a mixture of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.1 g, 0.313 mmol) and triethylamine (0.065 mL, 0.47 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature under argon for ˜15 h, then diluted with water and DCM. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography. Elution with EtOAc/petroleum ether yielded the title compound as a yellow oil (0.127 g). δH (CDCl3, 400 MHz) 8.51 (1H, d), 7.75 (1H, dd), 7.67 (2H, m), 7.55 (1H, d), 7.40 (1H, m), 7.24 (2H, d), 7.08 (1H, m), 7.03 (2H, d), 4.15 (1H, br.s), 3.78 (1H, d), 3.53 (3H, s), 3.45 (1H, d), 3.32 (1H, d), 3.06 (1H, td), 2.69 (1H, d), 2.49 (1H, d), 2.09 (1H, dd), 1.98 (1H, m), 1.44 (9H, s), 1.16 (3H, d). MS (ES): MH+ 519.3.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1/[C:5](/[O:11][CH3:12])=[CH:6]\[C:7]([O:9][CH3:10])=[O:8].[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[Br-:1].[CH3:12][O:11]/[C:5](/[C:4]1[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=1[CH2:2][P+:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:6]/[C:7]([O:9][CH3:10])=[O:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)/C=C(/OC)c1ccccc1CBr
Solvent: C1CCOC1
Product: COC(=O)/C=C(/OC)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 82.7 %

Procedure:
115 g (0.4 mol) of methyl (E)-2-bromomethyl-β-methoxycinnamate and 105 g (0.4 mol) of triphenylphosphine in 700 ml of tetrahydrofuran are refluxed for 24 h. Filtration with suction and washing with tetrahydrofuran result in 181 g (82% yield) of (E)-2-(1-methoxy-2-methoxycarbonylethenyl)benzyltriphenylphosphonium bromide in the form of colorless crystals with melting point 189°-192° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:34]1[CH2:39][CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35]1.O1CCOCC1>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.CO.O>[O:34]1[CH2:39][CH2:38][CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C@:15]4([CH2:19][S:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:35]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: NC1=N[C@@]2(CS1)c1cc(-c3cncc(F)c3)ccc1Oc1ncc(Br)cc12
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: O
Solvent: CO
Product: NC1=N[C@@]2(CS1)c1cc(-c3cncc(F)c3)ccc1Oc1ncc(C3=CCCOC3)cc12
Temperature: 100 °C
Yield: 50 %

Procedure:
A microwave vial was charged with (S)-3-bromo-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (90 mg, 0.20 mmol), potassium carbonate (140 mg, 1.02 mmol), 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (85 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium(0) (23.46 mg, 0.020 mmol), dioxane (1.35 mL) and water (0.68 mL). The reaction was heated in the microwave at 100° C. for 40 min. After cooling for rt, the organic layer was separated with a separatory funnel, dried over sodium sulfate, filtered, and concentrated to afford a yellow oil which was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-100% EtOAc in 90:10 CH2Cl2:CH3OH to provide a white solid, (S)-3-(5,6-dihydro-2H-pyran-3-yl)-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (45 mg, 0.10 mmol, 50% yield). MS m/z=447.2 [M+H]+. Calc'd for C24H19FN4O2S: 446.5.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](OB(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].C[C:14]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[CH2:24](O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.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>[CH:1]([C:3]1[CH:4]=[C:5]([C:21]2[CH:20]=[CH:19][C:15]([C:16]([O:18][CH3:24])=[O:17])=[CH:14][CH:22]=2)[CH:6]=[CH:7][CH:8]=1)=[O:2]
Reactant: O=Cc1cccc(OB(O)O)c1
Reactant: CCO
Reactant: Cc1cc(Br)ccc1C(=O)O
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: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cccc(C=O)c2)cc1
Temperature: 100 °C

Procedure:
A solution of tetrakis(triphenylphosphine)palladium (297 mg) was added to a solution of 3-formylphenylboric acid (3.00 g) and methyl 4-bromobenzoic acid (4.30 g) in a mixture of toluene (30 ml), ethanol (50 ml) and saturated aqueous sodium hydrogencarbonate solution (30 ml) at ambient temperature. The mixture was heated at reflux for 2 hours at 100° C. The reaction mixture was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to afford the title compound (3.37 g) as colorless crystals.