Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7](O)=O)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]2[NH:17][C:7]([CH:4]3[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]3)=[N:18][C:13]=2[CH:12]=1
Reactant: O=C(O)C1CCNCC1
Reactant: Nc1ccc(F)cc1N
Product: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 180 °C

Procedure:
To a mixture of piperidine-4-carboxylic acid (18.33 g, 0.14 mol) and 4-fluoro-benzene-1,2-diamine (18.01 g, 0.14 mol) was added polyphosphoric acid (138.39 g) and the mixture heated at 180° C. (internal temperature) for 2 h 45 minutes. The reaction mixture was cooled, reheated to 80° C. and the reaction was quenched by cautious addition to water (300 mL). The mixture was made basic (pH 8) by the addition of concentrated aqueous NaOH. The aqueous phase was extracted sequentially with 3:7 isopropanol:CH2Cl2 (2×200 mL) and CH2Cl2 (150 mL) and the combined organic phase dried (Na2SO4) and concentrated. The aqueous phase was reextracted with n-butanol (2×200 mL), the organic layer dried (Na2SO4) and concentrated. The crude product was stirred in diethyl ether, filtered and dried to give crude 5-fluoro-2-piperidin-4-yl-1H-benzoimidazole. Further purification was achieved by preparing the hydrochloride salt.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1.Cl.[OH:44][CH:45]1[CH2:48][NH:47][CH2:46]1.CN(C=O)C>CCOC(C)=O>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([OH:26])([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)[C:27]3[CH:28]=[N:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)[CH:8]=2)[N:3]=[C:2]([N:47]2[CH2:48][CH:45]([OH:44])[CH2:46]2)[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: OC1CNC1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CC(O)C3)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (100 mg, 0.164 mmol, Intermediate 65), 3-hydroxyazetidine hydrochloride (189 mg, 1.64 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 24 hours. The reaction solution was taken up into EtOAc, transferred to a reparatory funnel and extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C33H27ClF3N7O2, 645.2. m/z found, 646.3 [M+H]+. 1H NMR (600 MHz, CD3OD) δ ppm 8.78 (d, J=2.0 Hz, 1H), 8.13 (dd, J=2.5, 0.4 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 8.01 (dd, J=8.2, 2.0 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J=1.4 Hz, 1H), 7.64-7.59 (m, 2H), 7.57 (dd, J=8.8, 2.2 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.50-6.46 (m, 1H), 6.35 (s, 1H), 4.55-4.49 (m, 1H), 4.39-4.34 (m, 2H), 4.34 (s, 2H), 3.99-3.93 (m, 2H), 3.48 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+].O>ClC1C=CC=CC=1Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([O:9][CH3:10])=[C:6]([N:7]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:8]=1
Reactant: ClCCNCCCl
Reactant: COc1c(N)cc(Br)cc1C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Temperature: 200 °C
Reaction time: 22 h
Yield: 116.7 %

Procedure:
5-Bromo-3-(tert-butyl)-2-methoxyaniline (311 g) and bis(2-chloroethyl)amine hydrogenchloride (251 g) were suspended in 4 L of 1,2-dichlorobenzene, and the mixture was vigorously stirred for 22 hours at an external temperature of 200° C. The mixture was cooled to room temperature, and then potassium carbonate (620 g) and water were added and extraction was performed with methylene chloride (6 L). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to yield a black oil (460 g). Purification was performed by NH-silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (161 g) as blackish purple solid (41%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C1CCCCC=1>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=2)[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][N:23]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=Cc1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(F)(F)F)cn3)cc12
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)CCc1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(F)(F)F)cn3)cc12
Temperature: 135 °C

Procedure:
A mixture of 3-(2-ethoxycarbonylvinyl)-1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)indole-2-carboxylic acid ethyl ester (150 mg, 0.26 mmol, see step (c) above), Pd—C (10%), cyclohexene (1.2 mL) in absolute EtOH was heated under microwave irradiation at 135° C. for 1 h. The mixture was filtered through Celite® and the solids were washed with EtOAc. The combined filtrates were concentrated to give the sub-title compound. Yield 150 mg (100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:20][N:8]2[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O.[NH2:32][NH2:33]>CO>[CH2:12]([O:11][C:10]1[C:9](=[O:19])[N:8]2[CH:20]=[C:21]([CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:22]=[CH:23][C:7]2=[N:6][C:5]=1[C:3]([NH:32][NH2:33])=[O:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 3-benzyloxy-7-morpholin-4-ylmethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester (AU2007001980) (1 g, 2.44 mmol) in methanol (15 ml), hydrazine hydrate (1.44 g, 85% content, 24.4 mmol) was added at room temperature. The mixture was stirred for 1 hour. After most of the solvent was evaporated under reduced pressure, 15 ml of water was added. The mixture was extracted with dichloromethane three times, and the extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness to give the titled product (807 mg, 80.7%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][NH:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OC1C2N=NNC=2C=CC=1.CN(C1C=CC=CN=1)C.C(Cl)CCl>O1CCCC1>[C:18]1([NH:17][C:8]([C:7]2[C:2](=[O:1])[NH:3][CH:4]=[C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=2)=[O:10])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc(-c2ccccc2)c[nH]c1=O
Agent: CN(C)c1ccccn1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)c1cc(-c2ccccc2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
To a solution of 2-Oxo-5-phenyl-1,2-dihydro-pyridine-3-carboxylic acid (44 g, 0.20 mmol) in tetrahydrofuran (5 mL) were successively added aniline (20 μL, 0.23 mmol), hydroxybenzotriazole (30 mg, 0.23 mmol), dimethylaminopyridine (27 mg, 0.23 mmol) and EDC (43 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with DCM containing 10% of MeOH to afford the title compound as a white solid (20 mg, 34% yield). MS (ES+) 291. δH (DMSO-d6) 7.2 (3H, m), 7.9 (1H, t), 8.5 (1H, d), 8.6 (2H, m), 9.3 (1H, s).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1([CH3:31])[CH:7]([CH:8]=C(C)C)[CH:6]1[C:12]([O:14][CH:15]([C:29]#[N:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]>C(OCC)(=O)C>[CH3:4][C:5]1([CH3:31])[CH:7]([CH:8]=[O:1])[CH:6]1[C:12]([O:14][CH:15]([C:29]#[N:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]
Reactant: O=[O+][O-]
Reactant: CC(C)=CC1C(C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Solvent: CCOC(C)=O
Product: CC1(C)C(C=O)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Yield: 72 %

Procedure:
Ozone gas was bubbled at -78° C. into a solution of 1.88 g (5.00 mmol) of cyano(3-phenoxyphenyl)methyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate obtained in Reference Example 3, in 10 ml of ethyl acetate. The subsequent operation was conducted in the same manner as in Reference Example 5, whereby 1.26 g of cyano(3-phenoxyphenyl)methyl 2,2-dimethyl-3-formylcyclopropanecarboxylate was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1)=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cncnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cc1cncnc1
Temperature: 0 °C
Yield: 92.6 %

Procedure:
Under nitrogen atmosphere to a solution of (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(pyrimidin-5-ylmethyl)pyrrolidine (21.0 g) in dichloromethane (105 ml) were added triethylamine (16.1 g) firstly and methanesulfonyl chloride (13.7 g) secondly at 5° to 10° C. After the reaction mixture was stirred for an hour at the same temperature, dichloromethane (50 ml) and ice-water (150 ml) were added thereto, and then the solution was stirred vigorously for twenty minutes. The organic layer was separated and washed with 1N-hydrochloric acid (100 ml), 1N-sodium hydroxide (200 ml), and brine (200 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-(pyrimidin-5-ylmethyl) pyrrolidine (25.2 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH3:15])=[O:13].[C:16]([Cu])#[N:17].[C-]#N.[Na+]>CN(C=O)C.O>[C:16]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH3:15])=[O:13])#[N:17]
Reactant: COC(=O)c1cccc2c(Br)cccc12
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2c(C#N)cccc12
Yield: 94.7 %

Procedure:
A mixture of methyl 5-bromo-1-naphthylcarboxylate (5.2 g, 19 mmol) and CuCN (3.4 g, 38 mmol) in 100 mL anhydrous DMF was refluxed overnight. After cooling the reaction to 70° C., a solution of NaCN (2 g) in 50 mL water was added to destroy the copper complex. Ethyl acetate was added and the two layers were separated. The organic layer was washed with brine, dried over MgSO4, and concentrated. Silica gel column chromatography using hexane/ethyl acetate (5/1) gave the product (3.8 g, 95%).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([Mg]Br)[CH3:11].B(F)(F)F.[OH-].[Na+]>C(OCC)C.C(OCC)(=O)C>[CH2:7]([C:8]1([NH2:9])[CH2:11][CH2:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[Mg]Br
Reactant: N#CCc1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NC1(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of phenylacetonitrile (3 g, 25.61 mmol) and tetraisopropylorthotitanate (8 ml, 27.15 mmol) in diethyl ether (Et2O)/tetrahydrofuran (THF) (1/1, 100 ml) ethyl-magnesiumbromide (49.33 mmol) was added at room temperature. The exothermic mixture was stirred for 1 h at room temperature. Then BF3×Et2O (49.34 mmol) was added and the mixture was stirred for 1 h. The mixture was poured into a cold aqueous solution of NaOH (10%) and diluted with ethyl acetate. The mixture was filtered, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow oil (3.6 g, 96%).
Reaction SMILES: [NH2:1]C1SC2C=C([N+]([O-])=O)C=CC=2N=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[C:14]([NH2:1])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Solvent: O
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a suspension of 2-amino-6-nitrobenzothiazole (Sigma Aldrich, 2.93 g, 15 mmol) in pyridine (20 mL), benzoyl chloride (1.74 mL, 15 mmol) was added. After stirring over-night at r.t., additional benzoyl chloride (1.74 mL, 15 mmol) was added and the mixture was stirred at 60° C. After completion of the reaction, the mixture was poured into water (250 mL) and stirred overnight at r.t. Separation of the resulting precipitate yielded N-6-nitrobenzotihiazol-2-yl)benzamide (3.87 g, 12.9 mmol, 86%) as a yellow solid. LC/ESI-MS: m/z=300 [M+H]+; m/z=298 [M−H]−; Rt=3.93 min.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:40])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][C:35]([F:38])([F:37])[F:36])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:39])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:39][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:40])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:35]([F:37])([F:36])[F:38])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccccc3OC(F)(F)F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.28 mmol) was added to a stirred solution of {6-fluoro-3-methyl-4-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.038 g, 0.071 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-fluoro-3-methyl-4-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.034 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s., 1 H) 8.35 (d, J=7.82 Hz, 1 H) 8.06 (d, J=7.82 Hz, 2 H) 7.97-8.03 (m, 1 H) 7.91 (br. s., 2 H) 7.74 (t, J=7.90 Hz, 1 H) 7.59-7.67 (m, 1 H) 7.55 (d, J=7.82 Hz, 2 H) 7.38 (t, J=8.20 Hz, 1 H) 6.60 (d, J=10.80 Hz, 1 H) 3.84 (s, 2 H) 2.04 (s, 3 H). MS calcd. for C26H17F4O5S [(M−H)−] 517, obsd. 517.3.
Reaction SMILES: [C:1]([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1>C(Cl)Cl>[C:1]([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:42][O:43][CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][O:45]4)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2)NOC1CCCCO1
Yield: 51.9 %

Procedure:
A suspension of (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (200 mg, 0.50 mmol) in DCM (5 ml) was treated with TEA (0.11 ml, 0.82 mmol) and then with EDC (158 mg, 0.827 mmol), HOBt (107 mg, 0.793 mmol) and NH2OTHP (74 mg, 0.63 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (120 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:7]2=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:7]2
Reactant: COc1c(C)ccc2c1CC(Oc1ccc([N+](=O)[O-])cc1)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)ccc2c1CC(Oc1ccc([N+](=O)[O-])cc1)C2
Temperature: 62.5 °C
Yield: 70.3 %

Procedure:
To a mixture of 4-Methoxy-5-methyl-2-(4-nitro-phenoxy)-indan-1-one (1.8 gm, 0.0057 mole) and Triethyl silane (9.0 ml, 0.0564 mole), Trifluoroacetic acid (18 ml) was added at 20-25° C. The reaction mixture was heated to 60-65° C. for 3 hours and then poured into saturated Sodium bicarbonate solution. It was extracted with Ethylacetate (2×100 ml), dried over Sodium sulphate, distilled under vacuum to give a crude product which was purified by column chromatography using Ethyl acetate:Hexane (2:98) as a mobile phase. The collected fractions were distilled under vacuum to give 1.2 gm of desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cncc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
5-Bromo-3-pyridinamine (5 g) was dissolved in pyridine (150 ml) and the reaction was cooled to 0° C. in an ice-bath and stirred for 5 min. Benzenesulfonyl chloride (1.86 ml) was added dropwise and the reaction was stirred at 0° C. for 3 hr. Further benzenesulfonyl chloride (1.86 ml) was added and the reaction continued stirring for 1 hr. The reaction was neutralised with 2 M HCl and extracted with DCM (60 ml) then evaporated to dryness. The residue was dissolved in DCM and preadsorbed on fluorosil then purified by column chromatography on silica, eluting with 1-5% MeOH/DCM, to give the title compound (8 g).
Reaction SMILES: [Br:1]Br.[CH:3]1[C:4]2[N:5]([CH:10]=[N:11][CH:12]=2)[C:6](=[O:9])[NH:7][N:8]=1.O>C(O)(=O)C>[Br:1][C:12]1[N:11]=[CH:10][N:5]2[C:4]=1[CH:3]=[N:8][NH:7][C:6]2=[O:9]
Reactant: O=c1[nH]ncc2cncn12
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]ncc2c(Br)ncn12
Reaction time: 1 h

Procedure:
A solution of bromine (8.0 gm., 0.05 mole) in acetic acid (10 ml.) is added to a mixture of imidazo[1,5-d]-as-triazin-4(3H)-one (6.8 gm., 0.05 mole) and acetic acid (500 ml.). The reaction mixture is stirred for 1 hour, poured into water and extracted with chloroform. The aqueous layer is separated, made slightly alkaline and extracted with ether. Evaporation of the chloroform and the ether layers yields 5.0 gm. of a solid (46.3%). This solid is recrystallized to afford the title product, a cream colored solid, m.p. 244°-245° C.(d).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:29][CH2:30][CH2:31][N:32]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34](OCC)=[O:35].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:29]2[CH2:30][CH2:31][N:32]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34]2=[O:35])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CCOC(=O)CN(CCN)C(=O)OCC[Si](C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(OC)c1nc2c(cc1CN1CCN(C(=O)OCC[Si](C)(C)C)CC1=O)CCCN2
Reaction time: 12 h

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 2.50 g, 10.58 mmol), ethyl 2-((2-aminoethyl)((2-(trimethylsilyl)ethoxy)carbonyl)amino)acetate para-toluene sulphonate (intermediate 124, 8.37 g, 18.09 mmol) and triethylamine (3.23 ml, 23.28 mmol) in 1,2-dichloroethane (10 ml) at room temperature was stirred for 12 h and sodium triacetoxyborohydride (4.72 g, 21.16 mmol) added. The reaction mixture was stirred for 18 h at room temperature, partitioned between saturated aqueous NaHCO3 solution and EtOAc, the EtOAc phase washed with brine, dried over MgSO4 and evaporated. The residue was applied to a RediSep® silica column and purified by normal phase chromatography, eluting with a gradient from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a yellow oil. (UPLC-MS 6) tR 0.42; ESI-MS 322.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10](OS(C(F)(F)F)(=O)=O)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=1.CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:31][CH:32]=3)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2)C(F)(F)F
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Temperature: 110 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A 8-mL vial was charged with [2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate (100 mg, 0.243 mmol, 1 eq.), 2-(4-aminophenyl)acetic acid (37 mg, 0.245 mmol, 1 eq.) and DMSO (1 ml). The resulting mixture was stirred at 110° C. under Ar for 6 hr. After cooling to room temperature, water was added to the mixture (15 ml). The precipitate was collected by filtration and washed with water (15 ml). After drying, the title compound was obtained (97.5 mg, 97% yield). The product thus obtained was forwarded to the next step without any further purification.