Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([O-:11])([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:3].CCN(CC)CC.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C1COCC1.CC#N>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][C:20]([N:8]2[CH2:9][CH2:10][CH:5]([O:4][N+:2]([O-:11])=[O:3])[CH2:6][CH2:7]2)=[O:21])=[CH:28][CH:27]=1)([O-:31])=[O:30]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])OC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To a solution of Piperidin-4-yl nitrate hydrochloride (INTERMEDIATE 13, Step B) (0.40 g, 2.20 mmol) and Et3N (0.67 g, 6.60 mmol) in THF/CH3CN 2/1 (24 mL) was added 4-Nitrophenyl chloroformate (0.44 g, 2.20 mmol) as solid. After stirring at rt over night, the mixture was concentrated. The residue was diluted with EtOAc and washed with NaH2PO4 5%. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column SNAP 50; TLC method: n-hexane/ethyl acetate 7/3; Rf=0.37), affording the title product as a white solid. 1H-NMR (300 MHz, CDCl3); δ 8.36-8.25 (2H, m), 7.39-7.28 (2H, m), 5.30-5.18 (1H, m), 4.00-3.50 (4H, m), 2.20-2.06 (2H, m), 2.02-1.86 (2H, m).
Reaction SMILES: [CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([C:21]#[C:22][C:23]1([OH:27])[CH2:26][CH2:25][CH2:24]1)=[N:8][C:9]=2[Cl:20])[CH:2]=[CH2:3].O.[NH3:29]>COCCOC.[Cl-].[NH4+].C(OCC)(=O)C>[ClH:20].[CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([CH2:21][CH2:22][C:23]1([OH:27])[CH2:26][CH2:25][CH2:24]1)=[N:8][C:9]=2[NH2:29])[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2cccc(F)c2)nc2c(Cl)nc(C#CC3(O)CCC3)nc21
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCn1c(-c2cccc(F)c2)nc2c(N)nc(CCC3(O)CCC3)nc21
Product: Cl

Procedure:
A suspension of 1-{2-[9-allyl-6-chloro-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol (45 g, 116.8 mmol) in 1,2-dimethoxyethane (900 ml)/conc. ammonia water (450 ml) was stirred in an autoclave at 70° C. for 5 hours. After cooling as it was, the reaction solution was diluted with an aqueous saturated ammonium chloride solution (×1) and ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution (×1), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in diethyl ether, and the solid was collected by filtration and washed with diethyl ether, to give the title compound in free form (31.3 g, 98%). This free compound was suspended in 300 ml ethanol, dissolved by adding 26 ml of 5N hydrochloric acid, and concentrated. The residue was washed with diethyl ether and dried, to give 30 g of the title compound (yield 64%)
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7](=[O:18])[N:6]([CH3:19])[C:5](=[O:20])[CH:4]=1)[NH2:2].O=P(Cl)(Cl)Cl.[CH3:26]O>CN(C=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:3]3[NH:1][N:2]=[CH:26][C:4]=3[C:5](=[O:20])[N:6]([CH3:19])[C:7]2=[O:18])=[CH:11][CH:12]=1
Reactant: COc1ccc(Cn2c(NN)cc(=O)n(C)c2=O)cc1
Reactant: CO
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn[nH]c32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 6-hydrazinyl-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (0.45 g, 1.6 mmol) in DMF (2 mL), POCl3 (0.3 mL, 3.3 mmol) is added dropwise at 0° C. After the reaction mixture is stirred at 0° C. for 1 hour, the mixture is treated with methanol carefully to give white solid. The solid is further purified by chromatography to give 0.4 g product (Yield: 85%). 1H NMR (DMSO-d6) 153.23 (s, 3H), 3.71 (s, 3H), 5.05 (s, 2H), 6.85 and 7.31 (AB, 4H, J=11.6 Hz), 8.47 (s, 1H), 13.5 (br, 1H). MS (FAB) m/z 287.21 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1.[Cl:19]CCl>>[Cl:19][CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1
Reactant: CCOC(=O)c1cccnc1-n1ccc(CO)n1
Reactant: ClCCl
Product: CCOC(=O)c1cccnc1-n1ccc(CCl)n1
Yield: 101.7 %

Procedure:
To a solution of ethyl 2-(3-(hydroxymethyl)-1H-pyrazol-1-yl)nicotinate (3.76 g, 13.69 mmol) in dichloromethane (100 mL) thionyl chloride (1.1 mL, 15.07 mmol) was added dropwise under stirring. After the reaction was completed, the mixture was concentrated and purified by chromatography over silica gel (eluent CH2Cl2+0-5% methanol) to give 3.7 g of the title compound as clear oil; ESI-MS [M+H]+: 266.1. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.64 (dd, 1H), 8.49 (d, 1H), 8.13 (dd, 1H), 7.53 (dd, 1H), 6.65 (d, 2H), 4.23 (q, 2H), 1.17 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[OH:24].C[O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=3[F:16])[CH:6]=[N:5]2)[C:27]([OH:26])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Oc1cccc(F)c1F
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(F)c2F)cc1=O
Yield: 63 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,3-difluoro-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2,3-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (14.91 g, 63%) as a white solid; ESI-MS 364 [M+H+]; HPLC: >95% (purity). 1H-NMR (300 MHz, CDCl3) δ 7.89-7.90 (d, 1H), 7.12-7.19 (m, 2H), 6.99-7.03 (m, 1H), 6.01 (s, 1H), 5.51-5.56 (m, 1H), 2.29-2.39 (m, 1H), 2.07-2.16 (m, 1H), 1.50-1.81 (m, 7H), 1.10-1.25 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:25](=O)[CH:26]([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH2:25]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C=O
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(C)CN1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL scintillation vial were mixed N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide (100 mg, 0.312 mmol), isobutyraldehyde (0.343 mmol), and sodium triacetoxyborohydride (0.43 mmol) in anhydrous dichloroethane (4 ml). The reaction mixture was stirred overnight at room temperature. This mixture was diluted with water and the resulting suspension was stirred again overnight at room temperature. The solid was filtered through a 30 mL plastic disposable Buchner funnel, and the collected solid was washed with water, dried for 2 hours, washed with ether, and dried again to provide the title compound. 1H NMR (400 MHz, DMSO-d6, Temp=90° C.) δ ppm 8.58 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.18 (m, 1H), 7.50 (m, 2H), 7.38 (d, J=5.1 Hz, 1H), 7.30 (m, 2H), 6.03 (m, 1H), 4.80 (m, 4H), 3.06 (m, 2H), 2.61 (t, J=5.6 Hz, 2H), 2.44 (m, 2H), 2.17 (d, J=7.2 Hz, 2H), 1.82 (m, 1H), 0.89 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 377 (M+H).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH3:44][O:45][C:46]1[CH:51]=[C:50]([C:52]([OH:54])=O)[CH:49]=[C:48]([N:55]2[CH2:59][CH2:58][CH2:57][C:56]2=[O:60])[N:47]=1.[CH:61]12[CH2:67][CH:64]([CH2:65][CH2:66]1)[CH2:63][CH:62]2[NH:68][C:69](=[O:84])[C@H:70]([CH3:83])[CH2:71][C@H:72]([OH:82])[C@@H:73]([NH2:81])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>>[CH2:74]([C@H:73]([NH:81][C:52]([C:50]1[CH:49]=[C:48]([N:55]2[CH2:59][CH2:58][CH2:57][C:56]2=[O:60])[N:47]=[C:46]([O:45][CH3:44])[CH:51]=1)=[O:54])[C@@H:72]([OH:82])[CH2:71][C@H:70]([C:69](=[O:84])[NH:68][CH:62]1[CH2:63][CH:64]2[CH2:67][CH:61]1[CH2:66][CH2:65]2)[CH3:83])[C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: COc1cc(C(=O)O)cc(N2CCCC2=O)n1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: COc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)n1

Procedure:
Prepared in an analogous manner to E6, from 2-methoxy-6-(2-oxopyrrolidin-1-yl)pyridine-4-carboxylic acid (D58) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10](#[N:13])[CH:11]=[CH2:12].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO.C(OCC)(=O)C>[C:10]([CH2:11][CH2:12][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])#[N:13]
Reactant: Cc1ccc(C)c(O)c1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(OCCC#N)c1

Procedure:
A mixture of 15.0 g of 2,5-dimethylphenol, 16.17 mL of acrylonitrile, and 0.75 mL of Triton-B (a 40% solution of benzyltrimethylammonium hydroxide in methanol) is heated to reflux overnight. The mixture is diluted with ethyl acetate and washed four times with 5% aqueous sodium hydroxide solution, two times with 3N hydrochloric solution, and two times with water. Drying of the organic layer with sodium sulfate, followed by filtration and evaporation provides 17.4 g of 1-(2-cyanoethoxy)-2,5-dimethylbenzene as a brown oil.
Reaction SMILES: O1CCCC1.C([NH:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:17]([F:35])=[CH:16][C:15]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40])=[O:37])C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].CO>[NH2:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[C:17]([F:35])=[CH:16][C:15]=1[C:36]([NH:38][C:39]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([CH3:40])[CH3:41])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(NCc2ccccc2)c(C(=O)NC(C)(C)c2ccccc2)cc1F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(N)c(C(=O)NC(C)(C)c2ccccc2)cc1F
Yield: 72.1 %

Procedure:
Palladium hydroxide (0.29 g) was added to a solution of tetrahydrofuran (7.2 ml) and methanol (14.3 ml) containing tert-butyl cis-2-(6-benzylamino-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (1.43 g), followed by stirring at room temperature for 1 hour in a hydrogen atmosphere. Insoluble matter was removed by filtration, and filter cake was washed with ethyl acetate. The filtrate was mixed with the washing solution, and the solvent was distilled away under reduced pressure. Diisopropylether and hexane were added to the obtained residue, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(6-amino-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (870 mg) was thus obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:28])[CH:22]=1)=[O:17]>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH:19]4[CH2:20][CH:18]4[C:16]([OH:17])=[O:15])=[CH:22][C:23]=3[F:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCC1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 84 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.032 g, 0.15 mmol) obtained in Step C of Preparation Example 23 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.037 g, 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[Li]CCCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: Nc1ccc(Br)cc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(N)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a solution of 4-bromo-2-fluoro-phenylamine (114 g, 0.6 mol) in anhydrous THF (750 mL) under inert atmosphere at −78° C. was added a 1.6M solution of nBuLi in hexanes (1500 mL, 2.4 mol) dropwise keeping the internal temperature below −60° C. The reaction mixture was treated dropwise with TMSCl (256 mL, 2.0 mol), keeping the internal temperature below −60° C. The reaction mixture was allowed to warm to 0° C. over a 1 hour period and poured into ice-cold 2M HCl (ca 1 L). The mixture was vigorously stirred for 10 min, then the organic layer was separated, washed with water followed by a saturated solution of potassium carbonate, dried (Na2SO4), filtered and concentrated to give the title compound as a light brown oil (89 g, 81%).
Reaction SMILES: C1COCC1.[BH4-].[Na+].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][CH:12]=1)([O-])=O>CO.[Ni](Br)Br>[NH2:8][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(CNc2ccccn2)cc1
Agent: Br[Ni]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(CNc2ccccn2)cc1
Yield: 46.1 %

Procedure:
To a solution of nicke l bromide (44 mg) in methanol (4 ml)/THF (4 ml) was added sodium boro hydride (40 mg), and the mixture was stirred. To the mixture was added 2-[(4-nitrophenyl)methylamino]pyridine (0.92 g) and then sodium boro hydride (414 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added nickel bromide (44 mg)and sodium boro hydride (454 mg), and the mixture was stirred at room temperature for 2 hours. Insoluble materials were filtered off with sellaite, and to the filtrate was added sodium bicarbonate solution. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried (anhydrous magnesium sulfate) and concentrated, and the residue was purified twice with silica gel column chromatography (ethyl acetate/hexane=1/1) to give 2-[(4-aminophenyl)methylamino]pyridine (369 mg) as pale red solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.C[N+](C)=[CH:8][Cl:9].[Cl-].[F:12][CH2:13][C:14]1([CH2:21][F:22])[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C=O>[Cl:9][C:8]1[CH2:18][CH2:19][C:14]([CH2:21][F:22])([CH2:13][F:12])[CH2:15][C:16]=1[CH:17]=[O:20]
Reactant: O=C1CCC(CF)(CF)CC1
Reactant: C[N+](C)=CCl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1=C(Cl)CCC(CF)(CF)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 100 mL pear flask was added N,N-dimethylformamide (498 μl) and dichloromethane (8.9 mL) to give a colorless solution. The solution was cooled to 0° C. and POCl3 (550 μl) was added dropwise and then the mixture was warmed to room temperature for 30 minutes. In the meantime, to a 100 mL pear shaped flask was added EXAMPLE 353C (870 mg, 5.36 mmol) in dichloromethane (8941 μl) to give a colorless solution. The Vilsmeier reagent was then taken up in a syringe and added dropwise to the 4,4-bis(fluoromethyl)cyclohexanone (870 mg) solution at room temperature. The resulting solution was stirred overnight. The reaction was poured into saturated aqueous NaHCO3 and ice, warmed to room temperature and extracted with dichloromethane (3×30 mL). The organics were combined, dried over MgSO4, filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix (0-60% hexanes/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25]C(=O)[CH2:23][CH2:22]2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:28][N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH3-][C:37]#N.[Na+].[ClH:40]>C(Cl)Cl.CO>[ClH:1].[ClH:40].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][CH:28]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH2:31][CH2:30]3)[CH2:23][CH2:22]2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CN1CCCNCC1
Reactant: [BH3-]C#N
Reactant: O=C1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCCN(C2CCC(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)CC2)CC1
Reaction time: 96 h
Yield: 39 %

Procedure:
To a mixture of 5-chloro-2-[4-oxocyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzamide (600 mg, 1.5 mmol), 1-methyl-hexahydro-1,4-diazepine (0.57 mL, 4.6 mmol), methanol (30 mL) and methylene chloride (15 mL) was added NaCNBH3 (66 mg, 1.05 mmol) and the mixture was stirred for four days. To the reaction mixture was added additional 1-methyl-hexahydro-1,4-diazapine (0.19 mL, 1.5 mmol) followed by NaCNBH3 (22 mg, 0.35 mmol) and the mixture was stirred for 1 day. The reaction mixture was acidified with 1 N HCl, stirred for 1 h, and then concentrated in vacuo. To the residue was added methylene chloride and the resulting solution was washed with satd Na2CO3 solution. The organic layer was concentrated and chromatographed on 60 g silica gel (CH2Cl2 to 5% 2 M NH3/MeOH in CH2Cl2) followed by further HPLC purification (Vydac C18; 5% CH3CN/(0.1% TFA in H2O) to 70% CH3CN/(0.1% TFA in H2O).; Rt: 20.3 min) to give the title compound as a solid (340 mg, 39%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O.B(O)(O)O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:8][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1ccc[nH]1
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: c1c[nH]c(-c2nc3ccccc3o2)c1
Yield: 51.6 %

Procedure:
2-(Pyrrol-2-yl)benzoxazole was prepared as follows: A mixture of 5.55 g (0.05 mol) of pyrrole-2-carboxylic acid and 5.46 g (0.05 mol) of o-aminophenol and 3.09 g (0.05 mol) boric acid in 50 mL of xylene was heated under reflux for 3 days while removing water which was generated from reaction using a Dean-Stark trap. The cooled reaction mixture was diluted with 100 mL of ethyl acetate, washed with 150 mL of 5% sodium hydroxide solution and then with 150 mL of water. The separated organic layer was dried over anhydrous sodium sulfate. The resulting crude product was purified by column chromatography on silica gel with 20% hexane in chloroform as eluant. The desired product, 2-(pyrrol-2-yl)benzoxazole (4.75 g, 52%), was obtained as a white solid. m.p. 149°-150° C.; 1H NMR (CDCl3) δ6.38-6.40 (m, 1H, ArH), 7.05-7.06 (m, 1H, ArH), 7.11-7.13 (m, 1H, ArH), 7.29-7.36 (m, 2H, 2xArH), 7.53-7.56 (m, 1H, ArH), 7.65-7.69 (m, 1H, ArH), 10.9 (bs, 1H, NH).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.[Cl:15][S:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([CH3:29])=[CH:22][N:23]=[CH:24]2)(=[O:18])=[O:17]>>[ClH:15].[CH3:14][C@@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[S:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([CH3:29])=[CH:22][N:23]=[CH:24]2)(=[O:17])=[O:18]
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: Cc1cncc2cccc(S(=O)(=O)N3CCNC[C@H]3C)c12
Product: Cl
Yield: 26.5 %

Procedure:
Using 0.34 g of (R)-1-(tert-butoxycarbonyl)-3-methylpiperazine and 0.40 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.15 g of the objective compound (white crystals).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=[O:22])=[CH:13]1>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:21]=[O:22])=[CH:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Yield: 61.6 %

Procedure:
The same procedures used in Example 7 were repeated except for using 5.96 g of 4-nitrobenzyl bromide and 2.00 g of indole-3-carbaldehyde as a starting material to give 2.38 g of 1-(4-nitrobenzyl) indole-3-carbaldehyde as pale brown crystals. The yield thereof was found to be 62%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](Cl)[C:12]#[CH:13].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:13]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:12]#[CH:11]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: C#CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNc1ccc(C(C)=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of 25 g (0.185 mol) of 4-aminoacetophenone, 12.7 ml (0.176 mol) of propargyl chloride, and 35 ml of diisopropylethylamine in 500 ml of dry toluene is stirred at 60° C. for eight hours then at 90° C. for twenty-four hours. The reaction is cooled to room temperature and poured into a saturated sodium bicarbonate solution. The organic portion is separated and concentrated in vacuo to an orange oil. The oil is chromatographed on silica gel eluting with a gradient of 20-50% ethyl acetate in hexane. The appropriate fractions are concentrated to leave a pale yellow solid. The solid is recrystallized from ethanol to give two crops of the desired product, 14.99 g (49% yield); mp 97°-100° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:12]1[O:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)o1
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)o1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is washed with dichloromethane.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.C(O[C:22]([NH:24][CH2:25][CH:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27]([OH:29])=[O:28])=O)C1C=CC=CC=1.COC(=O)CN1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O.Cl[C:64]1([N+:70]([O-:72])=[O:71])[CH:69]=[CH:68][CH:67]=[N:66]C1>>[C:34]([O:33][C:31]([NH:30][CH:26]([CH2:25][NH:24][C:22]1[C:64]([N+:70]([O-:72])=[O:71])=[CH:69][CH:68]=[CH:67][N:66]=1)[C:27]([OH:29])=[O:28])=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])C1(Cl)C=CC=NC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Product: CC(C)(C)OC(=O)NC(CNc1ncccc1[N+](=O)[O-])C(=O)O

Procedure:
(2S) 2-tert-Butoxycarbonylamino-3-(3-nitropyridin-2-ylamino)propionic acid was prepared by a similar method as (2S) 2-tert-butoxycarbonylamino-3-(2-nitrophenyl-amino)propionic acid in Step A of the synthesis of 600a, except that 3-chloro-3-nitro pyridine was used instead of 2-fluoronitrobenzene, to give 4.05 g (64%) of a yellow solid.