Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:28])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][CH:19]=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=2[CH3:22])=[O:16])=[CH:8][C:7]=1[CH3:27].[C:29](O)(=[O:32])[CH2:30][OH:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[OH:32][CH2:29][C:30]([NH:1][CH2:2][CH:3]([OH:28])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][CH:19]=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=2[CH3:22])=[O:16])=[CH:8][C:7]=1[CH3:27])=[O:31]
Reactant: O=C(O)CO
Reactant: Cc1cc(CCC(=O)c2scc(CC(C)C)c2C)cc(C)c1OCC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(CCC(=O)c2scc(CC(C)C)c2C)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a solution of rac-3-[4-(3-amino-2-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-isobutyl-3-methyl-thiophen-2-yl)-propan-1-one (353 mg, 0.876 mmol) in DCM (10 mL), glycolic acid (127 mg, 1.67 mmol) followed by DIPEA (521 mg, 4.03 mmol) and TBTU (439 mg, 1.37 mmol) is added and the reaction mixture is stirred at rt for 16 h. The mixture is diluted with DCM and washed twice with water. The aq. washings are extracted three times with DCM. The combined organic extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with EA containing 0 to 100% of MeOH to give racemic 2-hydroxy-N-(2-hydroxy-3-{4-[3-(4-isobutyl-3-methyl-thiophen-2-yl)-3-oxo-propyl]-2,6-dimethyl-phenoxy}-propyl)-acetamide (160 mg) as a beige solid; LC-MS: tR=0.99 min, [M+1]=462.40; 1H NMR (D6-DMSO): δ 7.66 (t, J=5.9 Hz, 1H), 7.45 8s, 1H), 6.86 (s, 2H), 5.63 (s br, 1H), 5.26 (s br, 1H), 3.91-3.83 (m, 1H), 3.79 (s, 2H), 3.63-3.55 (m, 2H), 3.45-3.36 (m, 1H), 3.22-3.12 (m 1H), 0.310-3.04 (m, 2H), 2.80-2.73 (m, 2H), 2.40-2.37 (m, 5H), 2.15 (s, 6H), 1.76 (m, J=7.0 Hz, 1H), 0.85 (d, J=6.4 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH:28]=[CH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:16][N:17]3[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:36]OS(OC)(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:36][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:28]=[CH:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:16][N:17]2[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])=[CH:13][CH:12]=1
Reactant: COS(=O)(=O)OC
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(Nc3cccc([N+](=O)[O-])c3)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1

Procedure:
To (3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine (434 mg, 0.89 mmol) in THF (5 mL) cooled to −5° C. under an atmosphere of argon, was added dimethylsulfate (0.42 mL, 4.5 mmol) followed by LiHMDS (1M in THF) (1.8 mL, 1.8 mmol). After 20 min the reaction was quenched with saturated NH4Cl(aq) (2 mL), then extracted 3×20 mL EtOAc. The pooled organic material was washed with brine (10 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (eluting with hexane:EtOAc 9:1) gave methyl-(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-amine, as an oil (367 mg, 82%): TLC (Hexane:EtOAc 7:3) Rf sm 0.29, Rf p 0.39 (ethyl acetate:hexane 3:7); FTIR (KBr) 2951, 2894, 1611, 1528, 1485, 1348, 1248, 1077 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.99 (d, 1H, J=8.67 Hz) 7.77 (t, 1H, J=2.25 Hz), 7.72 (dd, 1H, J=0.79, 2.09 Hz), 7.60, (d, 2H, J=7.22 Hz), 7.26–7.54 (m, 7H), 7.19 (dd, 1H, J=0.78, 2.41 Hz) 7.07 (dd, 1H, J=1.85, 8.69 Hz), 5.70 (s, 2H), 3.63 (t, 2H, J=8.10 Hz), 3.48 (s, 3H), 0.92 (t, 2H, J=8.10 Hz), −0.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.2, 149.6, 147.1, 143.5, 142.5, 137.3, 131.9, 129.8, 129.0, 128.2, 126.8, 123.1, 122.6, 120.2, 120.0, 119.7, 114.4, 111.4, 104.5, 78.0, 66.8, 41.1, 18.0, −1.2; LCMS (ESI) [M+H]/z Calc'd 501. Found 510.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:29]([O:36][CH2:37][C@@H:38]1[C@@H:43]([O:44][CH3:45])[C:42]([CH3:47])([CH3:46])[CH2:41][CH2:40][C@H:39]1[CH:48]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC>[CH3:45][O:44][C@H:43]1[C:42]([CH3:46])([CH3:47])[CH2:41][CH2:40][C@@H:39](/[CH:48]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C@@H:38]1[CH2:37][O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CO[C@@H]1[C@@H](COCc2ccccc2)[C@H](C=O)CCC1(C)C
Reactant: CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCC/C=C/[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a stirred solution of n-octyltriphenylphosphonium bromide (313 mg) in dry tetrahydrofuran (0.5 ml) and dry HMPA (0.5 ml), n-BuLi (0.44 ml, 1.6M solution in n-hexane) was added at 0° C. After the mixture was stirred at 0° C. for 30 min, a solution of (1R,2R,3R)-2-(benzyloxymethyl)-3-methoxy-4,4-dimethylcyclohexane-1-carbaldehyde (68 mg) in dry tetrahydrofuran (0.5 ml) was added to the resulting orange solution. The mixture was stirred at 0° C. for 30 min, and at room temperature for 2 hrs. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (using n-hexane:ethyl acetate= 10:1 as an eluent) to give benzyl [(1R,2R,6S)-2-methoxy-3,3-dimethyl-6-[(E)-1-nonenyl]cyclohexyl]methyl ether (54 mg 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[O:22])[CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[O:22])[CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)CC1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(CC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 45.2 %

Procedure:
Using 3-[2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]-2-oxoethyl]piperidine (140 mg, 0.418 mmol) and 3-(methoxycarbonyl)phenylboric acid (150 mg, 0.836 mmol), the same procedure was followed as in Example 2 to give 88.7 mg (45%) of the desired compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([C:25](O)=[O:26])[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7].Cl.[O:29]([NH2:31])[CH3:30]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([C:25]([NH:31][O:29][CH3:30])=[O:26])[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CSc1nc(C(=O)O)cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)n1
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)nc(SC)n1

Procedure:
Title compound was synthesized by an analogous method to Example 8 by coupling 6-(4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(methylthio)pyrimidine-4-carboxylic acid (Example 35) with methoxylamine hydrochloride (commercially available).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]1[C:11]2([CH2:14][CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:12]2)[CH2:10]1.CI>C1COCC1>[CH3:2][C:13]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12][C:11]2([CH2:10][CH2:9]2)[CH2:14]1
Reactant: O=C(OCc1ccccc1)C1CC2(CC2)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)OCc2ccccc2)CC2(CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of LDA (3.47 mL, 6.94 mmol 2M in THF) in THF (5 mL) cooled to −78° C., was added dropwise a solution of benzyl spiro[2.3]hexane-5-carboxylate (0.5 g, 2.312 mmol) in THF (2 mL). The resulting solution was stirred for 30 min. prior to the dropwise addition of MeI (0.723 mL, 11.56 mmol) at −78° C. The resulting reaction mixture was allowed to warm to RT and stir for 12 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (20 mL) and extracted with EtOAc (3×10 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 5% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford the Intermediate 317A as a colorless liquid (200 mg, 38% yield). MS(ES): m/z=231.2 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.50-7.28 (m, 5H), 5.36-4.94 (s, 2H), 2.87-2.47 (m, 2H), 2.01-1.77 (m, 2H), 1.62-1.39 (s, 3H), 0.60-0.22 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O>CS(C)=O>[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][N:35]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NN2CCOCC2)s1
Solvent: CS(C)=O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NN2CCOCC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 74.1 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (29 mg, 0.1 mmol) in dimethyl sulfoxide (4.0 mL) was heated with 5-(hydrazinocarbonyl)thiophene-2-carboxylic acid morpholin-4-ylamide (27 mg, 0.1 mmol) prepared in Reference Synthetic Example 11 at 100° C. for 20 hours and allowed to cool to room temperature 2 mL of water was added, and the precipitated solid was collected by filtration, washed with chloroform and dried Synthesis was carried out in the same manner as in Reference Synthetic Example by using to give 40 mg of the desired product (yield 73%).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=S)SC1=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
A solution containing 2.1 g (0.0157 mol) of rhodanine, 2.76 g (0.0151 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.15 ml of piperidine in 10 ml of acetic acid was heated for 7-8 h at 100° C. After cooling the crystalis were filtered and washed with 2-propanol. Yield 4.0 g (89%), mp>350° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34][CH2:35][C:36](Br)=[O:37].C(=O)([O-])O.[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:36](=[O:37])[CH2:35][Br:34])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1)OCc1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CBr)c3ccccc32)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a solution of (3aR*,10aS*)-9-[4-(benzyloxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (610 mg, 1.4 mmol) in dichloromethane (7 mL) was added bromoacetyl bromide (0.15 mL, 1.7 mmol) dropwise and the mixture was stirred at room temperature for 15 minutes. This reaction mixture was diluted with water (5 mL) with vigorous stirring and neutralized with sodium hydrogen carbonate. The aqueous layer was separated and the organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from chloroform-ethyl acetate to provide 519 mg (yield 66%) of the title compound. m.p. 222°-223° C. (decomp.).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH3:20][O:21]C1C=CC=C2C=1NC=C2>>[CH3:20][O:21][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: COc1cccc2cc[nH]c12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: COc1cccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-methoxy-1H-indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH2:21]([O:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([C:36]([C:38]2[CH:43]=[C:42](Cl)[N:41]=[CH:40][N:39]=2)=[O:37])=[CH:31][C:30]=1[CH3:45])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:21]([O:28][C:29]1[C:30]([CH3:45])=[CH:31][C:32]([C:36]([C:38]2[N:39]=[CH:40][N:41]=[C:42]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:43]=2)=[O:37])=[CH:33][C:34]=1[CH3:35])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc(C)c1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c(OCc5ccccc5)c(C)c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
200 mg (0.730 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 240 mg (0.680 mmol) (4-benzyloxy-3,5-dimethyl-phenyl)-(6-chloro-pyrimidin-4-yl)-methanone and 0.400 mL (2.30 mmol) DIPEA were combined in 2.0 mL DMF and stirred for 3 h at RT. The mixture was added to ice water, the precipitate was suction filtered and dried.
Reaction SMILES: C1O[C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[O:2]1.[NH3:13].COCCOCCOC>O>[NH2:13][C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[OH:2]
Reactant: N
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Solvent: O
Solvent: COCCOCCOC
Product: Nc1ccc([N+](=O)[O-])cc1O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.18 mol (30 g) of 3,4-methylenedioxynitrobenzene in a mixture of 240 ml of 28% strength ammonia solution and 240 ml of diethylene glycol dimethyl ether is heated at 100° C. for 28 hours in an autoclave. After cooling, 480 ml of water are added. The unreacted initial product precipitates. It is recovered by filtration and the filtrate is then neutralised with hydrochloric acid. After filtration, the filtrate is extracted with ethyl acetate. The ethyl acetate is driven off in vacuo. The residue is treated with 25 ml of acetic anhydride and then kept in a boiling water-bath for 30 minutes. After cooling, the expected product is isolated in the form of the acetyl derivative. This acetyl derivative is hydrolysed with 45 ml of hydrochloric acid of density 1.17, at 90° C. for one hour. After dilution and neutralisation of the solution containing hydrochloric acid, 2-amino-5-nitrophenol is isolated by filtration. Melting point=207° C.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([N:28]1[CH2:33][CH2:32][C:31]([F:38])([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]1)[CH2:26][CH3:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[OH-].[Na+]>CO.O>[F:44][C:42]([F:43])([F:45])[C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([C:2]([F:47])([F:46])[F:1])[CH:41]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[CH:25]([N:28]1[CH2:33][CH2:32][C:31]([F:38])([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1)[CH2:26][CH3:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CCC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N1CCC(F)(C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N1CCC(F)(C(=O)O)CC1
Yield: 406.7 %

Procedure:
To a solution of methyl 1-{1-[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl]-4-(trifluoromethyl)phenyl]propyl}-4-fluoropiperidine-4-carboxylate (example 204) (0.23 g, 0.33 mMol) in methanol was added 1N sodium hydroxide (1.8 mL.) and the solution was microwaved for 30 minutes at 100° C. The reaction mixture was diluted with water and the pH was adjusted to 3 and was extracted with dichloromethane. The organic extract was dried, concentrated and purified by flash chromatography to afford the title compound (0.9 g., 40%), 1HNMR (400 MHz. CDCl3) δ 7.90 (t, 1H), 7.80 (s, 1H), 7.60 (m, 37.15 (m, 1H), 4.70 (dd, 4H), 4.6 (m, 2H), 4.40 m, 2H), 4.10 (s, 3H), 3.80 (m, 1H), 2.90 (m, 1H), 3.60 (m, 2H), 2.40(m, 2H), 2.15 (m, 1H), 2.10 (m, 2H), 1.9 (m, 1H), 0.5 (t, 3H). MS (ES+) Calc 670.55, Found 671.4 (M+1)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:24]([O:8][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: OCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, benzyl alcohol and DBU in DME. ES-MS m/e (%): 313 (M+H+, 100).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][CH:11]=[C:12]([F:14])[CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O1CCOCC1.O.[Cu]Br>[Br:22][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][CH:11]=[C:12]([F:14])[CH:13]=2)[CH:7]=1
Reactant: Br
Reactant: N#Cc1ccc(F)cc1-c1cc(N)ccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(F)cc1-c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
5′-Amino-5,2′-difluorobiphenyl-2-carbonitrile (2.87 g, 12.5 mmol) was dissolved in hot 1,4-dioxane (4 ml), 48% aqueous hydrobromic acid (40 ml) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (0.86 g, 12.5 mmol) in water (1.5 ml) over 20 min. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (5.38 g, 37.5 mmol) in 48% hydrobromic acid (10 ml). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (500 ml) and extracted with ethyl acetate (2×300 ml). The combined organics were washed with 10% aqueous ammonia solution (200 ml), water (200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give a black solid. Purification by chromatography [silica gel, 2-6% EtOAc/isohexane (containing 0.5% methanol)] gave the title compound as a pale brown solid: 1H NMR (400 MHz, CDCl3) δ7.13 (1H, dd, J9, 9 Hz), 7.19-7.23 (2H, m), 7.52-7.60 (2H, m), 7.81 (1H, dd, J8, 5 Hz).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[S:29][C:30]([CH3:36])=[C:31]([C:33]([OH:35])=O)[N:32]=1)([CH3:27])[CH3:26].[O:37]1[C:42]2([CH2:47][CH2:46][N:45]([CH2:48][C:49]3[C:50]([F:58])=[C:51]([CH2:55][CH2:56][OH:57])[CH:52]=[CH:53][CH:54]=3)[CH2:44][CH2:43]2)[CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)CC)C>CN(C=O)C>[F:58][C:50]1[C:51]([CH2:55][CH2:56][OH:57])=[CH:52][CH:53]=[CH:54][C:49]=1[CH2:48][N:45]1[CH2:46][CH2:47][C:42]2([O:37][CH2:38][CH2:39][N:40]([C:33]([C:31]3[N:32]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:29][C:30]=3[CH3:36])=[O:35])[CH2:41]2)[CH2:43][CH2:44]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: Cc1sc(C(C)C)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1sc(C(C)C)nc1C(=O)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.175 g) was added in one portion to a stirred solution at 0° C. of 2-isopropyl-5-methylthiazole-4-carboxylic acid (example 69, step b) (0.066 mg) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.109 g) and triethylamine (0.148 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.155 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23](=[O:25])[CH3:24].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:22][C:23](=[O:25])[CH3:24])[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: CC(=O)CCl
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (950 mg, 4.94 mmol) and potassium carbonate (4.10 g, 29.64 mmol) in 12 mL DMF was treated with chloroacetone (787 μL, 9.89 mmol) and stirred at room temperature overnight. After this time, the mixture was cooled to 0° C. and treated with 50 mL H2O under rapid stirring. A precipitate formed and it was filtered then washed with 50 mL H2O. The solid was collected and dried under reduced pressure overnight (1.01 g, 82.1%). 1H-NMR (DMSO-d6) δ: 8.17 (d, J=2.4 Hz, 1H), 8.05 (dd, J=2.4, 8.7 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.33 (s, 2H), 3.05 (t, J=7.8 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 2.24 (s, 3H). MS (EI): 248 (M+).