Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1>C(OCC)(=O)C>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1)=[O:3])[CH3:6]
Reactant: Nc1cccc(S)c1
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1cccc(S)c1

Procedure:
12 ml of ethyl chloroformate are added dropwise to a solution of 25 g of 3-aminothiophenol in 150 ml of ethyl acetate at 50°, under gentle reflux. 50 ml of ethyl acetate are added and the reaction mixture is boiled under reflux for 5 minutes, cooled to 40° and filtered with suction. The filtrate is evaporated to dryness and the oily evaporation residue is chromatographed on silica gel using toluene as the solvent. 3-Ethoxycarbonylaminothiophenol is obtained by evaporating the eluate. 10 g of this product are mixed with 8 g of ethyl acetoacetate and the mixture is added dropwise to 153 g of polyphosphoric acid at 90°. The mixture is warmed for 2 hours at an internal temperature of 95° and the hot reaction mixture is poured into 2 liters of ice-water, the resulting mixture is stirred for 30 minutes and the precipitate which has separated out is filtered off with suction. 2-Methyl-7-ethoxycarbonylamino-4-oxo-4H- 1-benzothiopyran is thus obtained and after recrystallisation from 70 ml of ethanol this melts at 216°-218°. 15.6 g of this product are refluxed with 28.7 ml of sulfuric acid and 52 ml of acetic acid for 5 hours. The reaction mixture is poured into 500 ml of ice-water and the resulting mixture is neutralised with sodium hydroxide solution. 2-Methyl-7-amino-4-oxo-4H-1-benzothiopyran with a melting point of 165°-169° is obtained and this can be purified via the hydrochloride and then melts at 172°-175°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]([OH:9])[C:4]([CH3:11])([CH3:10])[N:3]=1.[C:12]1([CH2:22][CH2:23][Br:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[BrH:24].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]([O:9][CH2:23][CH2:22][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:4]([CH3:11])([CH3:10])[N:3]=1
Reactant: BrCCc1cccc2ccccc12
Reactant: CC1(C)N=C(N)N=C(N)N1O
Solvent: CN(C)C=O
Product: Br
Product: CC1(C)N=C(N)N=C(N)N1OCCc1cccc2ccccc12
Yield: 20.4 %

Procedure:
This compound was prepared in a manner analogous to that of Example 3, Step F, using 0.8 gram (0.005 mole) of 4,6-diamino-1,2-dihydro-1-hydroxy-2,2-dimethyl-1,3,5-triazine (prepared in Example 3) and 1.3 grams (0.006 mole) of 2-(naphth-1-yl)ethyl bromide (commercially available) in 15 ml of dimethylformamide. The reaction product was recrystallized from water, yielding 0.4 gram of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[2-(naphth-1-yl)ethoxy]-1,3,5-triazine hydrobromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[CH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)=O.C1C[O:21][CH2:20][CH2:19]1>>[NH:16]1[C:17]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[CH:7]=[CH:19][C:20]([O:4][CH2:2][CH3:5])=[O:21])[CH:14]=[CH:15]1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [K+]
Product: CCOC(=O)C=Cc1cccc2cc[nH]c12
Reaction time: 2 h
Yield: 80 %

Procedure:
A 1.0 M solution of potassium tert-butoxide in THF (12.0 mL, 12.0 mmol) was added to THF (50 mL) at −78° C. under N2 followed by triethyl_phosphonoacetate (2.6 mL, 13.1 mmol). A solution of 7-formylindole (1.01 g, 7.0 mmol) in THF (10 mL) was then added dropwise over 5 min. The resulting red solution was stirred for 2 h, quenched with saturated NaHCO3 (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with H2O (60 mL), brine (60 mL), dried (MgSO4) and concentrated to a brown oil. Flash chromatography (SiO2, 8%EtOAc/hexanes containing 2% TEA) gave the title compound (1.0 g, 80%) as a white solid. 1H NMR (300 MHz, CDCl3) 8.53 (bs, 1H), 7.98 (m, 1H), 7.71 (m, 1H), 7.42 (m, 1H), 7.27 (m, 1H), 7.14 (m, 1H), 6.60 (m, 1H), 6.51 (m, 1H), 4.31 (m, 2H), 1.40 (m, 3H).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.O>C1COCC1>[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:17]1([OH:20])[CH2:18][CH2:19][C:14]2([O:21][CH2:11][CH2:12][O:13]2)[CH2:15][CH2:16]1
Reactant: c1cscn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2nccs2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A solution of n-butyllithium (8.1 mL of 1.6 M solution in hexane, 12.92 mmol) was added to thiazole (1.0 g, 11.75 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (1.84 g, 11.75 mmol) in THF (10 mL) was added to the lithiated compound solution via syringe and stirred for 3 h at −78° C. Water (5 mL) was added, and the reaction mixture was warmed to room temperature and extracted using EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and chromatographed to yield 2.531 g of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol in 89% yield. MS (EI) calcd: (M+H)+=242.1. Found: 242.2.
Reaction SMILES: CCCCCC.[H-].[Na+].[NH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:24]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[CH2:36]Br)[C:29]([O:31][CH3:32])=[O:30])#[N:25]>CCOC(C)=O.CN(C=O)C>[C:24]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[CH2:36][N:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:29]([O:31][CH3:32])=[O:30])#[N:25]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CBr)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C#N)c1
Reaction time: 3.5 h

Procedure:
To a mixture of hexane washed 60% disp. NaH (40 mg, 1 mmol) and DMF (8 mL) was added HN(BOC)2 (203 mg, 0.93 mmol) and stirred for 30 m. The reaction was added methyl 3-cyano-4-(bromomethyl)benzoate (202 mg, 0.80 mmol). After 3.5 h, the reaction was diluted with EtOAc (40 mL) and washed with H2O (6×5 mL). The organic layer was MgSO4 dried and concentrated. The crude material was chromatographed (30 g silica, 10% EtOAc/hexanes) to give the title compound (quant.). IR(CHCl3): 1125, 1370, 1723, 1791, 3020 cm−1; NMR(300 MHz, CDCl3): 1.46 (s, 18H); 3.96 (s, 3H); 5.08 (s, 2H); 7.42 (d, 1H, J=8.4 Hz); 8.23 (d, 1H, J=8.4 Hz); 8.32 (s, 1H); MS(FD): 391.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9]12([C:19](Cl)=[O:20])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.C(OCC)C>C(N(CC)CC)C>[C:9]12([C:19]([C:5]3[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=3)=[O:20])[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH2:10]1)[CH2:18]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NC(=O)c1nc[nH]n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: NC(=O)c1n[nH]c(C(=O)C23CC4CC(CC(C4)C2)C3)n1

Procedure:
To a cooled, stirred mixture of 2 g. of 1,2,4-triazole-3-carboxamide and 5.4 g. of adamantylcarbonyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 23.5 hours. The mixture is filtered and the solid is washed successively with diethyl ether, cold water, diethyl ether and dried in vacuo for 3 hours yielding 4.5 g. of colorless solid. This solid is extracted with hot dry acetonitrile, cooled and washed with acetonitrile yielding 0.4 g. of colorless crystals. The remaining 3.5 g. of acetonitrile insoluble solid is further extracted with acetonitrile, yielding an additional 0.6 g. of product, m.p. 213°-216° C. (dec.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[NH:8][C:7]2=[O:17].I[CH:19]([CH3:21])[CH3:20].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[N:8]([CH:19]([CH3:21])[CH3:20])[C:7]2=[O:17]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1C(=O)c2cc(Cl)c([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaH (5.30 g, 0.132 mol) was added in portions to a solution of 5-chloro-6-nitroisoindoline-1,3-dione (20.0 g, 88.27 mmol) in 100 mL of anhydrous DMF at 0° C. under argon. The reaction mixture was then stirred at rt for 3 h. 2-Iodopropane (15.0 g, 106 mol) was added dropwise via a syringe at rt under argon. The resulted mixture was stirred for 6 h at rt, hydrolyzed by adding 200 mL of water. The precipitate was isolated, washed with water and dried under vacuum. The solid was purified by column chromatography (silica-gel, CH2Cl2/Acetone=19/1 v/v) to give a solid product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])O[C:10]=1[C:17]([NH:19][CH:20]1[CH2:23][CH2:22][CH2:21]1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH2:25]>CO>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:25]([CH3:24])[C:10]=1[C:17]([NH:19][CH:20]1[CH2:23][CH2:22][CH2:21]1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)o1
Reactant: CN
Solvent: CO
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)n1C
Temperature: 72.5 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of the compound from example 4 (2.616 g, 8.35 mmol, 1.0 equiv) in methanol (10 ml) was quickly added methylamine (2M in methanol, 20 ml, 40 mmol, 4.79 equiv). The sealed tube was stirred overnight at 70-75° C. The resulting brown solution was evaporated to dryness and purified by chromatography (EtOAc, then 1:4 MeOH/EtOAc) provided the titled compound (1.70 g, 62.24%) as a white solid. M.p. 221.3-222.4° C.; 1H-NMR (DMSO-d6, 400 MHz) δ 1.65-1.69 (m, 2H, cyclobutyl H), 1.90-1.95 (m, 2H, cyclobutyl H), 2.14-2.21 (m, 2H, cyclobutyl H), 2.31 (s, 3H, CH3), 3.42 (s, 3H, NCH3), 4.34-4.30 (m, 1H, CH), 5.05 (s, 2H, OCH2Ph), 6.22 (s, 1H, CH), 7.39-7.30 (m, 5H, ArH), 9.08-9.06 (d, 1H, J=7.08 Hz, NH); MS (m/z) 327 (M++1), 230, 166, 91.
Reaction SMILES: C(OC([NH:8]CC(O)=O)=O)(C)(C)C.C(N(CC)CC)C.[Cl:20]C(OCC(C)C)=O.[C:28]([NH:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])[C:37]=1[O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[Cl:59])[C:33]([OH:35])=[O:34])(=[O:30])[CH3:29]>C1COCC1.CCOC(C)=O>[ClH:20].[NH2:8][CH2:29][C:28]([NH:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])[C:37]=1[O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[Cl:59])[C:33]([OH:35])=[O:34])=[O:30]
Reactant: CC(=O)NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cl
Product: NCC(=O)NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a stirred solution of N-t-butyloxycarbonyl glycine under argon at −5° C. in THF (2 mL) was added triethylamine (60 μL, 0.5 mmol) and then isobutyl chloroformate (67 μL, 0.52 mL). The resulting slurry was stirred 20 min and a solution of Example 13 Part A compound (222 mg, 0.45 mmol) and triethylamine (70 μL, 0.6 mmol) in THF (1 mL) was added over 1 min. The reaction was allowed to warm to room temperature and stirred. After 1 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 102 mg (37% yield). LC/MS gave the correct molecular ion [(M+H)+=617] for the desired compound.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=3)=[N:19][CH:20]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:30]1([C:25]([C:24]2[CH:28]=[CH:29][C:21]([C:18]3[N:19]=[CH:20][C:15]([O:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:6])[CH2:12][CH2:11]4)=[CH:16][CH:17]=3)=[CH:22][CH:23]=2)=[O:27])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)O)cc3)nc2)CC1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.6 %

Procedure:
4-(5-{[(1-{[(1-Methylethyl)oxy]carbonyl}-4-piperidinyl)methyl]oxy}-2-pyridinyl)benzoic acid (0.05 g, 0.13 mmol) was added to a solution of pyrrolidine (0.01 g, 0.13 mmol) in DMF (2 mL), followed by addition of HATU (0.05 g, 0.13 mmol), and diisopropylethylamine (0.02 g, 0.13 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction was then purified by reverse-phase preparative HPLC using CH3CN:H2O gradient (0:100 to 90:10) with 0.05% TFA as a modifier. The resultant lyophilized material was converted to its free base by dissolving the solid in CH2Cl2, washing with saturated aqueous NaHCO3 and concentrating in vacuo to give the title compound (15 mg, 25%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.44 (d, 1H, J=2.9 Hz), 7.93 (d, 2H, J=8.4 Hz), 7.65 (d, 1H, J=8.6 Hz), 7.68 (d, 2H, J=8.4 Hz), 7.27-7.20 (m, 1H), 4.95-4.85 (m, 1H), 4.29-4.12 (m, 2H), 3.87 (d, 2H, J=6.4 Hz), 3.68-3.59 (m, 2H), 3.47-3.41 (m, 2 H), 2.78-2.72 (m, 2H), 2.04-1.78 (m, 7H), 1.34-1.28 (m, 2H), 1.22 (d, 6H, J=6.2 Hz); LRMS (ESI), m/z 452 (M+H).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]3[O:24][CH2:23]3)[CH:13]=[N:12][C:11]=2[N:10]([CH3:25])[C:8]1=[O:9].C[O:27]CCOC.C(=O)(O)[O-].[Na+]>O>[CH3:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:24])[CH2:23][OH:27])[CH:13]=[N:12][C:11]=2[N:10]([CH3:25])[C:8]1=[O:9]
Reactant: Cn1c(=O)c2c(ncn2CCCCC2CO2)n(C)c1=O
Reactant: COCCOC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: Cn1c(=O)c2c(ncn2CCCCC(O)CO)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.24 ml of perchloric acid (70% strength) was added dropwise with stirring in 5 minutes to a solution of 3.6 g of 1,3-dimethyl-7-(5,6-epoxyhexyl)xanthine in 280 ml of a mixture of ethylene glycol dimethyl ether and water (volume ratio 3:2) at room temperature. After stirring at room temperature for 16 hours, the mixture was neutralized with sodium bicarbonate solution and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (mobile phase: chloroform/ethanol, volume ratio 8/2) and recrystallization from ethyl acetate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O)[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH2:16][CH3:17])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Reactant: CCOc1ccccc1B(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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1-c1cc(C(C)(C)C)c(O)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 97.2 %

Procedure:
To a solution of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (8.22 g, 30 mmol) in DMF (90 mL) was added 2-ethoxyphenyl boronic acid (5.48 g, 33 mmol), potassium carbonate (4.56 g, 33 mmol), water (10 mL) and Pd(PPh3)4 (1.73 g, 1.5 mmol). The mixture was heated at 90° C. for 3 h under nitrogen. The solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried and purified by column chromatography (petroleum ether-ethyl acetate, 10:1) to afford 2-tert-butyl-4-(2-ethoxyphenyl)-5-nitrophenol (9.2 g, 92%). 1H NMR (DMSO-d6) δ 10.38 (s, 1H), 7.36 (s, 1H), 7.28 (m, 2H), 7.08 (s, 1H), 6.99 (t, 1H, J=7.35 Hz), 6.92 (d, 1H, J=8.1 Hz), 3.84 (q, 2H, J=6.6 Hz), 1.35 (s, 9H), 1.09 (t, 3H, J=6.6 Hz); ESI-MS 314.3 m/z (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([OH:18])=O)[C:10]=2[N:11]=1)=[O:5].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26]>C(Cl)Cl.O>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH:26][C:16]([CH:12]1[C:10]2[N:11]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:20])[CH3:19])[S:8][C:9]=2[CH2:15][CH2:14][CH2:13]1)=[O:18]
Reactant: CC(C)(C)CC(=O)Nc1nc2c(s1)CCCC2C(=O)O
Reactant: CN(C)CCCN
Solvent: O
Solvent: ClCCl
Product: CN(C)CCCNC(=O)C1CCCc2sc(NC(=O)CC(C)(C)C)nc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,1-Carbonyldiimidazole (CDI, 87 mg, 0.537 mmol) was added to a solution of 2-(3,3-dimethylbutyrylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (144 mg, 0.486 mmol) in CH2Cl2 (10 mL), and the resultant mixture was stirred for a period of 2 hours at room temperature. Following cooling of the suspension to 0° C., N,N-dimethyl-1,3-propanediamine (51 mg, 0.50 mmol), dissolved in CH2Cl2 (10 mL), was added dropwise over a period of 10 minutes. Following stirring for 1 hour at 0° C. and overnight at room temperature, a few drops of water were added, and the resultant mixture was extracted with CH2Cl2 (3×10 mL). Following drying of the organic phase over Na2SO4 and filtration, the solvent was removed and the residue was purified via column chromatography. The product 2-(3,3-dimethylbutyrylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid(3-dimethylaminopropyl)amide was obtained in a yield of 125 mg (corresponding to 68% of theory).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl.CO>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(C(=O)OC(C)(C)C)CC4)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCNCC4)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 34) (159 mg, 0.40 mmol) in dichloromethane (12 ml) was added trifluoroacetic acid (6 ml). The resulting mixture was stirred at room temperature for 30 minutes and then diluted with methanol. Reaction was purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and the solvent evaporated in vacuo to afford the title compound (D35). MS (ES+) m/e 296 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CSC
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a stirred solution of 1(benzyloxycarbonyl)-L-proline (15 g) in tetrahydrofuran (150 ml) at 0° C., borane-methylsulfide complex (9 ml, 95% in dimethyl sulfide) was added and the reaction mixture was stirred at room temperature for 8 h. At the end of this time the reaction was quenched with 10% AcOH in methanol and the solvent was removed under reduced pressure. The crude product thus obtained was diluted with CHCl3 and washed with water, dried (CaCl2) and the solvent was removed under reduced pressure to get 11.5 g (81%) of the title compound as a thick liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:6][CH:7]=1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][NH2:28].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([CH:8]2[N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[N:28]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(Br)cn1)C(F)(F)C(F)(F)F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cn2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
1-(5-Bromo-pyridin-2-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (936.0 mg, 2.8 mmol) prepared in Step 3, 2-chlorophenylhydrazine hydrochloride (508.0 mg, 2.8 mmol), and piperidine (560.0 uL, 5.7 mmol) were added to ethanol (28.4 mL). The reaction mixture was stirred at 60° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 450.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[N+](=[CH2:18])=[N-]>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:18])=[O:13]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CCCC(=O)c1ccccc1Br
Solvent: CCOCC
Product: COC(=O)CCCC(=O)c1ccccc1Br
Yield: 97 %

Procedure:
To 0.54g (2.0 mmol) of the product of Example 2 dissolved in ether was added an ethereal solution of excess diazomethane at 0° C. to produce a 97% yield of the ester as a yellow oil. The ester was used without further purification.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[F:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])[CH:9]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Fc1ccnc(CCl)c1
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2cc(F)ccn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-4-fluoropyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(4-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless solid: mp 228-231° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.52 (dd, J=8.38, 5.56 Hz, 1H), 7.24-7.14 (m, 2H), 7.06-6.90 (m, 3H), 6.85 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.30 (s, 1H), 5.15 (d, J=16.0 Hz, 1H), 5.02-4.91 (m, 2H), 4.67 (d, J=8.9 Hz, 1H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 171.0, 167.6, 158.9 (2), 155.3, 152.0 (2), 144.7, 141.9, 138.4, 132.2, 128.9, 124.0, 123.7, 120.9, 111.7, 111.0, 110.8, 109.7, 109.5, 109.3, 99.4, 80.1, 64.5, 63.9, 58.1, 45.8, 11.9; MS (ES+) m/z 404.9 (M+1).