Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl.O>[C:33]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[N:14]=[C:13]([CH3:28])[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:10])[CH:16]=3)[CH2:21]2)[CH2:27][CH2:26]1)(=[O:35])[CH3:34]
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(C)=O)CC4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.1 g, 0.215 mmol, Preparation #K. 1) and TEA (0.2 mL, 1.4 mmol, Sd Fine Chem) in DCM (10 mL) was added acetyl chloride (0.022 g, 0.28 mmol, Spectrochem). The reaction mixture was slowly warmed to RT and stirred for about 10 min. The reaction mixture was diluted with water (10 mL) and the product extracted with DCM (2×20 mL). The combined organic layers were washed with water (1×25 mL) followed by brine (1×50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified using silica gel column chromatography eluted in 50% EtOAc-hexane. The relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 6-(5-(1-acetylpiperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide as an off white solid 0.05 g (45%): 1H NMR (400 MHz, DMSO): δ 9.469 (t, J=5.6 Hz, 1H), 8.139 (s, 1H), 7.176-7.114 (m, 2H), 6.885 (brs, 1H), 4.679-4.660 (m, 1H), 4.483-4.467 (d, J=6.4 Hz, 2H), 4.436-4.406 (m, 1H), 3.815 (s, 3H), 3.496-3.424 (m, 2H), 3.295-3.239 (m, 2H), 3.194-2.978 (m, 1H), 2.753 (s, 3H), 1.983 (s, 3H), 1.909-1.621 (m, 3H), 1.243-1.189 (m, 2H). LC/MS (Table 1, method c) Rt=1.76 min; MS m/z: 470.1 (M+H)+.
Reaction SMILES: [C:1](/[CH:5]=[CH:6]\[C:7]1[CH:8]=[C:9]([CH2:21][C:22]([OH:24])=O)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][CH3:4])=[O:2].[CH3:25][NH:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:25][N:26]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:22](=[O:24])[CH2:21][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:7](/[CH:6]=[CH:5]\[C:1]([O:3][CH3:4])=[O:2])[CH:8]=1
Reactant: COC(=O)/C=C\c1cc(CC(=O)O)ccc1OCc1ccccc1
Reactant: CNCCc1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C\c1cc(CC(=O)N(C)CCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.85 g (5.69 mmoles) of cis-3-carbomethoxyvinyl-4-benzyloxyphenylacetic acid in 50 ml of CH2Cl2 is added 1.02 g (6.26 mmoles) if 1,1'-carbonyldiimadazole. After 15 minutes, 827 ml (5.69 mmoles) of N-methyl-N-phenethylamine is added. After 5 hours, the reaction mixture is concentrated in vacuo and is purified flash chromatography to yield cis-N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carbomethoxyvinyl)phenyl]acetamide which is used directly in the next step.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[C:17]3[C:12](=[C:13]([C:24]([OH:26])=O)[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:4][CH2:3]1.C1C=CC2N(O)N=[N:34]C=2C=1.C(Cl)CCl.N>O1CCOCC1>[O:1]=[S:2]1(=[O:27])[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[C:17]3[C:12](=[C:13]([C:24]([NH2:34])=[O:26])[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(-c2ccccc2)cc2c(C3CCCS(=O)(=O)CC3)c[nH]c12
Agent: N
Solvent: C1COCCO1
Solvent: ClCCCl
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCCS(=O)(=O)CC3)c[nH]c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
3-(1,1-Dioxido-4-thiepanyl)-5-phenyl-1H-indole-7-carboxylic acid (0.076 mmol), HOBT (10 mg, 0.074 mmol), EDC (15 mg, 0.078 mmol) were mixed together. A solution of 0.5 M NH3 in dioxane (1.5 mL) was added in, and the reaction was heated in a microwave at 120° C. for 10 minutes, then allowed to sit at room temperature overnight. The solvent was evaporated and the crude product was dissolved in DMSO and purified by Gilson HPLC (0.1% TFA, 10%-90% CH3CN, 10 minutes). The desired fractions were concentrated, giving 4 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:27])[C:10](=[O:28])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:16]=[C:17]3[C:12](=[N:13][CH:14]=2)[N:11]([CH3:27])[C:10](=[O:28])[CH:9]=[C:8]3[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:34]#[C:33][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:3]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c(=O)cc(-c2cccc(Br)c2)c2cc(C(=O)c3ccc(Cl)cc3)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)cc(-c2cccc(C#C[Si](C)(C)C)c2)c2cc(C(=O)c3ccc(Cl)cc3)cnc21
Temperature: 60 °C
Yield: 79.3 %

Procedure:
To a solution of compound I (1 g, 2.21 mmol) in THF (10.0 mL), TEA (4 mL) was added followed by (PPh3)4Pd (0.25 g, 0.22 mmol) and CuI (42 mg, 0.22 mmol). The mixture was degassed using N2 for 30 min and TMS-acetylene (0.92 g, 6.64 mmol) was added. The mixture was heated in a microwave oven at 60° C. for 30 min. The reaction mixture was diluted with EtOAc (25 mL) and passed through a pad of celite. The filtrate was concentrated. Purification of the crude product provided 825 mg (80%) of compound J.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.CC(N(C)C)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 24 h
Yield: 94 %

Procedure:
10 g of 4-nitrobenzoic acid chloride are slowly introduced into 7.4 g of 4-aminobenzoic acid and 36 ml of dimethylacetamide while maintaining the temperature at less than 25° C. After stirring for 24 hours, 50 ml of methylene chloride are added at 10° C. in order to precipitate the desired product. After washing with water and drying, 14.5 g of product are isolated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@@H:7]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:49][C:50]1[S:51][CH:52]=[C:53]([CH2:55][CH2:56]O)[N:54]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:29])[C@@H:7]([NH:19][S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:56][CH2:55][C:53]2[N:54]=[C:50]([NH2:49])[S:51][CH:52]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(O)cc1)NS(=O)(=O)c1ccccc1
Reactant: Nc1nc(CCO)cs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCc2csc(N)n2)cc1)NS(=O)(=O)c1ccccc1
Reaction time: 72 h

Procedure:
To a stirred solution of 5-2 (0.14 g, 0.32 mmol) and PPh3 (0.11g, 0.41 mmol) in THF (2 mL) at ambient temperature was added a solution of 5-4 (56 μg, 0.39 mmol) DEAD (67 μL, 0.42 mmol) in THF (2 mL) dropwise over a 15 min period. After 72 h, the reaction mixture was diluted with EtOAc and then washed with H2O, sat. NaHCO3, 10% KHSO4 and brine, dried (MgSO4) and concentrated. After two flash columns: silica, 85% EtOAc/hexanes; silica, 5% to 30% isopropanol/CHCl3), 5-5 was obtained as a yellow oil. Rf 0.19 (silica, 85% EtOAc/hexanes).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2].O.[C:19]([C@@:22]1([OH:37])[C@@H:26]([CH2:27][OH:28])[O:25][C:24](Cl)([C:29](=[O:31])[CH3:30])[C@:23]1([C:34](=[O:36])[CH3:35])[OH:33])(=[O:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@:24]2([C:29](=[O:31])[CH3:30])[O:25][C@H:26]([CH2:27][OH:28])[C@@:22]([C:19](=[O:21])[CH3:20])([OH:37])[C@@:23]2([C:34](=[O:36])[CH3:35])[OH:33])=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1(Cl)O[C@H](CO)[C@](O)(C(C)=O)[C@]1(O)C(C)=O
Reactant: CC(=O)Nc1nc(NC(C)=O)c2[nH]cnc2n1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1nc(NC(C)=O)c2ncn([C@]3(C(C)=O)O[C@H](CO)[C@](O)(C(C)=O)[C@]3(O)C(C)=O)c2n1
Reaction time: 8 h

Procedure:
The dried chloromercuri derivative (24 g., 0.05 mole) of 2,6-diacetamidopurine was refluxed in xylene using a Dean-Stark water separator. Freshly prepared triacetyl-D ribofuranosyl chloride in xylene was added to the hot chloromercuri derivative and the mixture was refluxed, in an oil bath, with vigorous stirring. After 41/2 hours the reaction mixture was allowed to stand overnight at room temperature and then filtered. The precipitate was extracted (several times) with warm CHCl3. The CHCl3 extract was washed successively with 30% aqueous KI (thrice), water (thrice) dried, charcoaled and filtered. The filtrate was evaporated in vacuo, and the residue on trituration with ether gave 14.3 g. (58%; m.p. 87°-92°) of 2,6-diacetamido-9-triacetyl-β-D-ribofuranosyl purine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH3:24][C:25](=O)[CH2:26][CH2:27][C:28](=O)[CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH:9]2[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([N:1]4[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]4[CH3:24])=[CH:7][CH:6]=3)[CH2:12][CH2:11][C:10]2=[O:13])=[CH:19][CH:18]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)CCC(C)=O
Reactant: CC(C)(C)c1ccc(C2C(=O)CCC2c2ccc(N)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(C2CCC(=O)C2c2ccc(C(C)(C)C)cc2)cc1

Procedure:
A mixture of Example 7H (300 mg, 0.976 mmol), hexane-2,5-dione (134 mg, 1.171 mmol) and p-toluenesulfonic acid (1.856 mg, 9.76 mol) in toluene (2 mL) was stirred at 110° C. for 1 hour. The mixture was concentrated in vacuo. The residue was directly used in the next step without further purification. LC/MS (ESI) m/z 386 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.Br[C:25]1C=C(C=C[CH:32]=1)C#N>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[CH:32][CH:25]=[C:21]([C:20]#[N:19])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: N#Cc1cccc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cccc(C#N)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=333.3 (M+H+).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])[CH:14]=1
Reactant: CCOP(=O)(OCC)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cc(O)ccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of diethyl 5-tert-butyldimethylsilyloxy-2-methylphenylphosphonate 1-3 (165 mg, 0.46 mmol) and 0.69 mL of a 1 M solution of tetrabutylammonium fluoride (0.69 mmol) in 4 mL of THF was stirred at rt for 1 h. The mixture was then diluted with EtOAc, washed with brine, dried (MgSO4) and evaporated. The resulting residue was subjected to MPLC on a 12 g column of SiO2 eluting with 35% EtOAc in hexanes (10 min) and then 50% EtOAc (10 min) to provide diethyl 5-hydroxy-2-methyl-phenylphosphonate 1-4 as an oil. 1H NMR (300 MHz, DMSO-d6): δ 1.23 (t, 6H, J=6 Hz), 2.36 (d, 3H, J=1 Hz), 3.9-4.0 (m, 4H), 6.87 (dd, 1H, J=8, 3 Hz), 7.12 (t, 1H, J=8 Hz), 7.20 (dd, 1H, J=14, 3 Hz), 9.55 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[O:19]=[C:20]([NH:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)[CH2:21][NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:38]3[CH2:39][CH2:40][C@@H:36]([NH:35][C:20](=[O:19])[CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=4)[CH2:37]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)C(=O)c1ccc(C2CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(C2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
100 mg (0.4 mmol) of N,N-dimethyl-4-(4-oxocyclohexyl)benzamide and 126 mg (0.4 mmol) of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide were dissolved in 10 mL of methylene chloride. To the solution was added 170 mg (0.8 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 2 h. Direct chromatography on silica gel gave the final desired product 45 mg (top spot on TLC and first peak on HPLC), yield: 22%. MS: 545 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH2:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)=[O:4].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH:15][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)OCCC2N
Product: COC(=O)c1ccc2c(c1)OCCC2NC(=O)OCc1ccccc1

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using 4-aminochromane-7-carboxylic acid methyl ester (1.4 g) and benzyloxycarbonyl chloride (2.0 ml), the objective 4-(benzyloxycarbonylamino)chromane-7-carboxylic acid methyl ester (1.9 g) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C)c1C(=O)O
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,6-Dimethylbenzoic acid (15 g, 99.88 mmol) was added to anhydrous CH2Cl2 (20 ml) at 0° C. followed by drop wise addition of oxalyl chloride (2M in CH2Cl2, 14.14 g) under argon. The reaction mixture was stirred at the same temperature for 30 minutes and then warmed to the room temperature for 1 hour, concentrated and used without purification.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O-])=O.C(N(CC)CC)C.[CH3:30][O:31][CH2:32]Cl>CN(C=O)C.C(=O)([O-])O.[Na+]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:30][O:31][CH3:32])=[O:21]
Reactant: COCCl
Reactant: O=C(O)CCCCCCc1ccc2ccccc2c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOC(=O)CCCCCCc1ccc2ccccc2c1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.3 %

Procedure:
7-(1-Nitro-2-naphthyl)heptanoic acid (2 g) and triethylamine (2.02 g) were dissolved in DMF (10 ml) followed by addition of chloromethyl methyl ether (0.802 g), and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with cold saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness. Using the residue, 10% palladium-on-carbon (0.23 g), and ethanol (23 ml), a catalytic hydrogenation reaction was carried out at atmospheric temperature and pressure for 18 hours. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to provide methoxymethyl 7-(1-amino-2-naphthyl)heptanoate (2.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:30][CH2:31][C:32]1[N:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][C:36]=1[CH3:37])(=O)=O>CC#N.C(OCC)C>[C:15]([O:14][C:12]([CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:30][CH2:31][C:32]3[N:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:35][C:36]=3[CH3:37])=[CH:3][CH:4]=2)[O:9][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc2c(c1)OCC(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
To a stirred solution of tert-butyl 7-hydroxychromane-3-carboxylate (2.5 g, 10 mmol) in CH3CN (20 ml), K2CO3 (4.1 g) and 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl methanesulfonate (3.7 g) were added and the reaction mixture was heated under reflux for overnight. The reaction mixture was cooled to room temperature and diluted with 100 ml of diethyl ether. The diluted solution was passed through a pad of silica and the silica was washed with more ether. The ether solution was evaporated to dryness and purified using silica chromatography. The product was isolated as a white sold (2.8 g, 64.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[N:15][CH2:14][CH:13]([O:16][CH3:17])[O:12][CH3:11]
Reactant: COC(CN)OC
Reactant: O=Cc1cc(Br)ccc1F
Solvent: Cc1ccccc1
Product: COC(CN=Cc1cc(Br)ccc1F)OC

Procedure:
A mixture of 5-bromo-2-fluorobenzaldehyde (15 g, 74 mmol) and 2,2-dimethoxy-ethylamine (7.77 g, 74 mmol) in toluene (142 mL) was heated to reflux for 30 minutes using a Dean-Stark trap to remove water. The solution was then concentrated under vacuum to provide 5-bromo-2-fluorobenzylidene-2,2-dimethoxyethylamine. 5-Bromo-2-fluorobenzylidene-2,2-dimethoxyethylamine and cold concentrated sulfuric acid (28 mL) were added separately, dropwise, over a period of 20 minutes to concentrated sulfuric acid (83 mL) at 140° C. The mixture was stirred at 135° C. for 30 minutes, allowed to cool, and carefully poured onto ice. Filtered to remove solids and the mixture was washed with dichloromethane. The aqueous layer was made basic by cautious addition of 50% sodium hydroxide solution, and extracted with diethyl ether. Combined ether layers were dried (MgSO4), filtered and concentrated under vacuum to provide 310 mg (2%) of the desired product. MS (ESI) m/e 226 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[CH:25]=1>>[OH:33][C@:29]([C:26]1[CH:25]=[C:24]([CH3:23])[O:28][N:27]=1)([CH3:30])[C:31]#[C:32][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1nc2n(c1C(F)(F)F)CCOc1ccc(Br)cc1-2
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(F)(F)F)n2CCO3)no1
Yield: 20 %

Procedure:
10-bromo-3-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 19 mg (20%) of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH:30]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:12]([C:10]1[N:9]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:30][CH:22]3[CH2:21][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)=[CH:18][CH:19]=2)[N:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)[CH3:13]
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: O=CC1Cc2ccccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCC2Cc3ccccc3C2)cc1

Procedure:
A solution of 3-(3-pyridyl)-5-ethyl-1-(4′-aminophenyl)pyrazole (185 mg, 0.7 mmol) and indane 2-carboxaldehyde (0.96 mmol, 140 mg) in methanol (9 mL) and acetic acid (1 mL) was stirred at room temperature for 30 min. Sodium cyanoborohydride (124 mg, 2 mmol) was added and stirring continued at room temperature. After 3 h the solvent was evaporated under vacuum, the residue was taken up in sodium bicarbonate solution (50 mL), and extracted with methylene chloride (3×50 mL). The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated. Chromatography of the residue over silica gel (eluant, 35% ethyl acetate in methylene chloride) gave the title compound which was taken up in 50% aqueous acetonitrile containing 1% trifluoroacetic acid and lyophilized to give a light yellow solid. 1H NMR (DMSO-d6) δ 1.2 (3H, t, J=7.5 Hz), 2.63 (2H, q, J=7.5 Hz), 2.7-2.76 (3H, m), 3.05-3.12 (4H, m), 6.71 (2H, d, J=8.7 Hz), 6.98 (1H, s), 7.12-7.14 (2H, m), 7.21-7.24 (4H, m), 7.84-7.88 (1H, m), 8.65 (1H, br, d, J=8.2 Hz), 8.71 (1H, d, J=5.1 ),9.2 (1H, s).