Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([N:12]=[C:13]=[O:14])[CH2:9][CH2:10][CH3:11]>CO.O1CCCC1>[CH2:8]([NH:12][C:13](=[O:14])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])[CH2:9][CH2:10][CH3:11]
Reactant: OCCNCCO
Reactant: CCCCN=C=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCNC(=O)N(CCO)CCO
Reaction time: 1 h

Procedure:
To a solution of 106 g of diethanolamine in 700 mL of methanol was added a solution of 99 g of n-butylisocyanate in 40 mL of tetrahydrofuran over 1 hour, holding the temperature below 30° C. After the addition, the mixture was stirred for 1 hour and then the solvent was removed by vacuum distillation to give a white solid, N′-butyl-N,N-bis(2-hydroxyethyl)urea.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:21](=[O:28])[CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:21](=[O:28])[CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:3][CH:4]=1
Reactant: CON(C)C(=O)Cc1cccs1
Reactant: Brc1ccc(C2OCCO2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)c1ccc(C2OCCO2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A 25 ml RB flask with a stirring bar was charged with 1-bromo-4-(1,3-dioxolan-2-yl)benzene (243 mg, 1.0 mmol), followed by anhydrous THF (5 mL). The mixture was cooled to −78° C. and n-butyllithium (687 μL of 1.6 M solution in hexanes) was added dropwise over 2 min. After stirring for 15 min. at −78° C., N-methoxy-N-methyl-2-(2-thienyl)acetamide (1-1) (185 mg, 1 mmol) was added in one portion. After another 30 min at −78° C., the mixture was quenched with sat. ammonium chloride (20 mL), extracted twice with ethyl acetate (10 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified via column chromatography over silica gel (0-50% ethyl acetate/hexanes) to give 1-[4-(1,3-dioxolan-2-yl)phenyl]-2-92-thienyl)ethanone (1-2). 1H NMR (CDCl3, ppm) δ: 7.98 (d, J=8.25 Hz, 2H), 7.45 (d, J=8.25 Hz, 2H), 7.15 (d, J=5.15 Hz, 1H), 6.86 (m, 1H), 6.83 (m, 1H), 5.77 (s, 1H), 4.38 (s, 2H), 4.01 (m, 4H).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.C([N:20]([CH2:23]C)CC)C.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1C(O)=O>CN(C)C=O>[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[N:20]=[C:23]=[O:8]
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C=Nc1cnc2ccccc2n1
Temperature: 0 °C
Reaction time: 2.33 h

Procedure:
Diphenylphosphoryl azide (1.23 mL) was added to a solution of triethylamine (800 ul) and 2-quinoxaline carboxylic acid 1 g (5.74 mmol) stirring in 10 mL of dry dimethylformamide in an icewater cooling bath (2°). The reaction was stirred for 2.33 h during which time the reaction was allowed to warm to 25°. The reaction was poured into ice water and extracted three times with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The crude azide was dissolved in 15 mL of benzene and heated at reflux for 1.5 h. The solvent was removed in vacuo to provide the desired solid isocyanate. FT IR indicated a strong isocyanate absorption.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:25])[CH:17]([NH:18][C:19](=[S:24])[CH2:20][CH2:21][CH:22]=[CH2:23])[C@H:4]2[S:3]1.C(O)(=O)C>CN(C)C=O.[Zn]>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:25])[CH:17]([NH:18][C:19](=[S:24])[CH2:20][CH2:21][CH:22]=[CH2:23])[C@H:4]2[S:3]1
Reactant: C=CCCC(=S)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=CCCC(=S)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12
Reaction time: 1 h
Yield: 94.4 %

Procedure:
Zinc powder (5.55 g) was added to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylate (5.55 g) in anhydrous dimethylformamide (55.5 ml) and then acetic acid (5.5 ml) was dropwise added to the solution, after which the mixture was stirred for 1 hour. After the reaction, zinc powder was filtered off and washed with ethyl acetate. The filtrate and the washings were combined, after which the solution was poured into a mixture of 5% hydrochloric acid (250 ml) and ethyl acetate (100 ml), and then extracted. The aqueous layer was further extracted twice with ethyl acetate. The ethyl acetate layer was combined, and the combined ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, and then dried over magnesium sulfate. After the solution was concentrated under reduced pressure till the volume of the solution becomes about 40 ml. Crystals precipitated were collected by filtration and washed with isopropyl ether and dried to give colorless crystals of 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid (3.69 g), mp 121° to 123° C. Moreover the filtrate was concentrated and the obtained crystals were washed with isopropyl ether and then dried to give 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid (0.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][C@H:9]([NH2:11])[CH2:8][CH2:7][N:6]1[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4].[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](O)=[O:31]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][C@H:9]([NH:11][C:30]([C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]=2[OH:19])=[O:31])[CH2:8][CH2:7][N:6]1[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)CCN1CC1CCCCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CCN1CC1CCCCC1

Procedure:
(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-piperidine-2-carboxylic acid methyl ester was prepared from (2S,4R)-4-amino-1-cyclohexylmethyl-piperidine-2-carboxylic acid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C25H33N2O4 [(M+H)+] 425, obsd. 425.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=1)(OC(C)(C)C)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:38].Cl.Cl.CCOCC.Cl>CCOCC.O.CO>[ClH:38].[ClH:38].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=1
Reactant: COC(=O)NCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COC(=O)NCc1cncc(OC[C@@H]2CCN2)c1
Yield: 99 %

Procedure:
The product of step 159a (0.23 g, 0.70 mmol) was deprotected and isolated as the free base in 99% yield according to the procedure of Example 20b, followed by conversion to the Dihydrochloride with excess HCl/Et2O. [α]D23 +12.46 (c 0.1, MeOH); 1H NMR (D2O, 300 MHz) δ 2.65-2.75 (m, 2H), 3.66 (s, 3H), 4.08-4.19 (m, 2H), 4.43 (s, 2H), 4.53-4.69 (m, 2H), 4.90 (m, 1H), 8.22 (s, 1H), 8.44 (s, 1H), 8.63 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 252 (M+H)+. Anal. Calcd for C12H17N3O3.2.5 HCl.1.5 H2O.0.4 Et2O: C, 40.93; H, 6.69; N, 10.53. Found: C, 40.96; H, 6.63; N, 10.46.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.[OH-].[K+]>CO>[C:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][C:3]([OH:17])=[O:2])#[N:16]
Reactant: COC(=O)CCc1c[nH]c2ccc(C#N)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]cc(CCC(=O)O)c2c1
Yield: 100.2 %

Procedure:
Methy-5-cyanoindole-3-propionate (200 mg) was saponified in MeOH (10 mL)/KOH (150 mg, 0.88 mmol) at rt for 18 h. The solution was concentrated in vacuo, dissolved in water and washed with chloroform. The acidic layer was acidified and extracted with ethyl acetate, dried with Na2SO4, filtered and concentrated in vacuo to afford 188 mg of product. 1H NMR (CD3OD) δppm 2.83 (t, 2H, J=6.6Hz), 4.43 (t, 2H, J=6.6 Hz), 6.6 (nd,1H, J3.2 Hz), 7.42 (d, 2H, J=7.3 Hz), 7.43 (s, 1H), 7.61 (d, 1H, J=7.3 Hz), 7.99 (s, 1H); LRMS ESI (M+H)+ 215.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[CH:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:10][CH:9]=1)=[O:6]
Reactant: [H][H]
Reactant: O=C(Nc1ccc(C=CCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(CCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Yield: 46.5 %

Procedure:
3-Fluoro-5-morpholin-4-yl-N-[4-(3-morpholin-4-yl-propenyl)-naphthalen-1-yl]-benzamide (56 mg, 117 μmol), is stirred under 1 atmosphere of hydrogen with 10% palladium on carbon (50 mg) in methanol (15 ml) at room temperature for 1 day. Celite° (1 g) is then added and the mixture filtered through a pad of Celite® and washed with methanol (2×10 ml). The filtrate is evaporated to dryness and the purified by column chromatography on silica gel eluted with 5% methanol in ethyl acetate to give 3-fluoro-5-morpholin-4-yl-N-[4-(3-morpholin-4-yl-propyl)-naphthalen-1-yl]-benzamide as a white powder (26 mg). 1H NMR 300 MHz (CDCl3) 8.04(d, 1H, J=11.5 Hz), 7.95(s, 1H), 7.7-7.8(m, 2H), 7.5(m, 2H), 7.35(d, 1H, J=8.6 Hz), 7.3(s, 1H), 7.0(d, 1H, J=10.1 Hz), 6.7 (d, 1H, J=13.0 Hz), 3.8(t, 4H, J=5.7 Hz), 3.7(m, 4H), 3.2(m, 4H), 3.1(t, 2H, J=7.2 Hz), 2.45(s, 6H), 1.9(m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=3)[N:7]=[C:6]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:5]=2[C:26](O)=[O:27])[CH2:3][CH2:2]1.Cl.Cl.[NH:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:41][CH2:40][CH2:39][C@H:38]2[CH2:42][OH:43])[CH2:33][CH2:32]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:18])([F:19])[F:17])[CH:10]=3)[N:7]=[C:6]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[C:5]=2[C:26]([N:31]2[CH2:32][CH2:33][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[CH2:42][OH:43])[CH2:35][CH2:36]2)=[O:27])[CH2:3][CH2:2]1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Reactant: O=C(O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Agent: Cl
Product: O=C(c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1)N1CCC(N2CCC[C@H]2CO)CC1
Yield: 56 %

Procedure:
In analogy to the procedure described in Example 160E, 5-cyclopropyl-3-pyridin-4-yl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid (Example 162D]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol dihydrochloride (Example 161A]) gave the title compound as a light brown oil (56%). MS: 556.2 (MH+).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([O:22][CH3:23])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:9])[C:4](=[O:24])O1.[CH2:26]=O.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CO>[CH3:23][O:22][N:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[C:8]([C:7]1[CH2:26][N:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:4](=[O:24])[C:5]=1[OH:6])=[O:9]
Reactant: C=O
Reactant: CON(Cc1ccc(C(F)(F)F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NCCN1CCOCC1
Solvent: CO
Product: CON(Cc1ccc(C(F)(F)F)cc1)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 75 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(4-trifluoromethyl-benzyl)-acetamide (0.41 g, 1.13 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.38 g (75% yield) of the title compound as crystals after chromatography on reversed phase silica gel; mp 119° C. (dec) (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 2.48 (4H, m, 2×NCH2), 2.58 (2H, t, J=6.3 Hz, NCH2), 3.64 (2H, t, J=6.3 Hz, NCH2), 3.67 (4H, m, 2×OCH2), 3.75 (3H, s, OCH3), 4.31 (2H, s, NCH2), 4.94 (2H, s, NCH2), 7.47 (2H, d, J=8.1 Hz, aromatics), 7.63 (2H, d, J=8.1 Hz, aromatics). Anal. Calcd for C20H24F3N3O5: C, 54.17; H, 5.46; N, 9.48. Found: C, 54.12; H, 5.57; N, 9.52.
Reaction SMILES: [CH2:1]1[O:24][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=4)=[N:11][NH:10][C:9](=[O:22])[CH2:8][C:7]=3[CH:23]=[C:3]2[O:2]1.O.NN.Cl>C(O)C.[Ni]>[NH2:19][C:15]1[CH:14]=[C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:24][CH2:1][O:2][C:3]4=[CH:23][C:7]=3[CH2:8][C:9](=[O:22])[NH:10][N:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Cc2cc3c(cc2C(c2cccc([N+](=O)[O-])c2)=NN1)OCO3
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.3 %

Procedure:
To a suspension of 7,8-methylenedioxy-1-(3-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (20 mg, 0.061 mmol) in ethanol (5 ml,) was added Raney Ni (54 mg), hydrazine hydrate (40 μL, 0.71 mmol), and 2N HCl (60 μL, 0.12 mmol). The mixture was stirred at room temperature for 24 h. The solid Ni was filtered out. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography (10:1 CHCl3 /EtOH) to afford the title compound as a tan solid (6 mg, 33%), mp: 118°-122° C. 1H NMR (CDCl3) 8.33 (s, 1H), 7.22-7.17 (m, 1H), 6.94 (s, 1H), 6.94-6.88 (m, 1H), 6.81 (s, 1H), 6.79-6.75 (m, 1H), 6.67 (s, 1H), 6.03 (s, 2H), 3.74 (brs, 2H), 3.44 (s, 2H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:11]=1[C:12]#[N:13].[C:19](=[O:21])=[O:20].O>C1COCC1.CCOCC>[C:12]([C:11]1[C:14]([Cl:18])=[C:15]([CH:16]=[CH:17][C:10]=1[Cl:9])[C:19]([OH:21])=[O:20])#[N:13]
Reactant: O=C=O
Reactant: N#Cc1c(Cl)cccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(Cl)ccc(C(=O)O)c1Cl
Reaction time: 1.5 h

Procedure:
A solution of lithium di-isopropylamide (2M in heptane, 25 ml) was added to a solution of 2,6-dichlorobenzonitrile (8.6 g) in THF while maintaining the temperature below -70° C. The mixture was stirred for 1.5 hours then poured onto solid carbon dioxide. It was stirred for 1 hour then diluted with ether. Water was added and the mixture was acidified to pH1. It was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 3-cyano-2,4-dichlorobenzoic acid (9.4 g) as a white solid mp 230°-232° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][C:34]1=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23][N:36]4[CH2:37][CH2:38][NH:33][C:34](=[O:39])[CH2:35]4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CCNC(=O)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using piperazin-2-one in Step 2. LC-MS Method 2 tR=1.213 min, m/z=519.23; 1H NMR (CDCl3) 1.46 (d, 3H), 2.13-2.27 (m, 3H), 2.35 (m, 2H), 2.75 (m, 1H), 2.88 (m, 1H), 3.20-3.39 (m, 3H), 3.51 (s, 2H), 3.66 (s, 2H), 5.54 (m, 1H), 6.94-7.05 (m, 6H), 7.14 (m, 2H), 7.25 (d, 2H), 7.37 (m, 2H), 7.85 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]([O:43][C:44]([NH:46][CH2:47][CH2:48][NH2:49])=[O:45])([CH3:42])([CH3:41])[CH3:40]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([NH:49][CH2:48][CH2:47][NH:46][C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3CCNC(=O)OC(C)(C)C)-c3cnccc3C(=O)c24)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCNc1ccc2c3c(nn2CCNC(=O)OC(C)(C)C)-c2cnccc2C(=O)c13
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A suspension of 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one of Example 3 (0.535 g) and N-(tert-butoxycarbonyl)ethylenediamine (prepared according to Synt. Comm., 20, 2559, (1990); 1.12 g) in dry pyridine (5.35 mL) is heated at 80° C. The dark solution obtained is held at this temperature for 5 hours, then it is concentrated to dryness and partitioned between brine (30 mL) and ethyl acetate (2×25 mL). The orange-red solid insoluble in the biphasic mixture is separated by suction filtration and dried at 40° C. under vacuum (0.43 g).
Reaction SMILES: [N:1]#[C:2][NH2:3].[F:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)N.[N+:12]([O-:15])([OH:14])=[O:13].C([O:18]CC)C>CCO>[N+:12]([O-:15])([OH:14])=[O:13].[F:4][C:5]1[CH:6]=[C:7]([NH:1][C:2]([NH2:3])=[O:18])[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOCC
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: NC(=O)Nc1cccc(F)c1

Procedure:
Cyanamide (1.3 mL, 16.8 mmol, 50% by wt. in water), 3-fluoroaniline (1.34 mL, 14 mmol), and 14 M nitric acid (1 mL, 14 mmol) were refluxed in EtOH (14 mL) for 15 h. The reaction was cooled and poured into diethylether. The resulting white suspension was filtered and dried under vacuum. Yield: 1.17 g (38%) of a white powder. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (brs, 1H), 7.43 (m, 5H), 7.16-6.90 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([N:11]([CH2:15][CH3:16])[CH:12]([CH3:14])[CH3:13])([CH3:10])[CH3:9].[CH2:17]1[S:21](=[O:23])(=[O:22])[O:20][CH2:19][CH2:18]1>C(#N)C>[S:21]([CH2:17][CH2:18][CH2:19][N:1]([CH2:14][CH2:12][CH2:13][S:21]([O-:23])(=[O:22])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:20])(=[O:23])=[O:22].[CH2:15]([NH+:11]([CH:12]([CH3:14])[CH3:13])[CH:8]([CH3:10])[CH3:9])[CH3:16].[CH2:17]([NH+:1]([CH:2]([CH3:3])[CH3:7])[CH:8]([CH3:10])[CH3:9])[CH3:18]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: CC[NH+](C(C)C)C(C)C
Product: O=S(=O)([O-])CCCN(CCCS(=O)(=O)[O-])c1ccccc1
Yield: 94 %

Procedure:
A mixture of aniline (7 mmol), N,N-diisopropylethylamine (DIPEA, 18 mmol) and propane sultone (16 mmol) was heated in a pressure tube in 10 mL of acetonitrile at 120-130° C. for 9 h under argon atmosphere. The solvent was evaporated and ethylacetate was added. The precipitated DIPEA bromide was filtered off and the filtrate was evaporated. The residue was treated with ether to give di[ethyl(diisopropyl)ammonium] 3-(3-sulfonatopropylanilino)-1-propanesulfonate as a white or pinky-white solid. Yield: 94%.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:16][NH2:17])([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N=C=N.[Cl:21][C:22]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>ClCCl>[Cl:21][C:22]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:23]=1[C:24]([NH:17][CH2:16][C:9]1([CH2:12][CH:13]([CH3:14])[CH3:15])[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]1)=[O:25]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CCS(=O)(=O)N1CCC(CN)(CC(C)C)CC1
Agent: N=C=N
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(CNC(=O)c2ccc(C(F)(F)F)cc2Cl)(CC(C)C)CC1
Reaction time: 0.5 h

Procedure:
In a large glass container with a Teflon cap was placed 1-[1-(ethylsulfonyl)-4-isobutylpiperidin-4-yl]methanamine (5) (670 mg, 2.55 mmol). This was dissolved in dichloromethane (50 ml) and PS-carbodiimide resin (5.11 mmol) was then added along with 2-chloro-4-(trifluoromethyl)benzoic acid (688 mg, 3.06 mmol). The lid was sealed and the bottle was shaken for 0.5 hours. The resin was filtered off and washed with EtOAc (3×25 ml). The organics were concentrated in vacuo to give an off white solid. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 2-chloro-N-{[1-(ethylsulfonyl)-4-isobutylpiperidin-4-yl]methyl}-4-(trifluoromethyl)benzamide (7) as a white solid. Calculated HRMS 469.1534 Found 469.15333. 1H NMR (300 MHz D6DMSO): δ 8.85 (s, 1 H), 7.95 (s, 1 H), 7.79 (d, J=7.8 Hz, 1 H), 7.60 (d, J=8.1 Hz, 1 H), 3.34 (s, 2 H), 3.21 (s, 4 H), 3.05 (q, J=7.2 Hz, 2 H), 1.75 (m, 1 H), 1.51 (m, 4 H), 1.29 (d, J=4.8 Hz, 2 H), 1.21 (t, J=7.5 Hz, 3 H), 0.94 (s, 3 H), 0.91 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O.[OH-].[Na+]>[C:1]1([C:7]2[C:15]([C:16](=[O:18])[CH3:17])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1c(-c2ccccc2)nn2ccccc12
Yield: 47.7 %

Procedure:
2-Phenylpyrazolo[1,5-a]pyridine (2.00 g) was added to a stirred solution of acetic anhydride (4.20 g) and two drops of sulfuric acid at room temperature. After being stirred under reflux for 14 hours, the reaction mixture was poured onto 80 ml of 4 N NaOH aqueous solution and extracted with chloroform (30 ml×2). The extracts were combined and washed with water (30 ml), saturated sodium chloride aqueous solution (30 ml), then dried over magnesium sulfate and evaporated in vacuo. The residual crystals were recrystallized from diisopropyl ether to give 2-phenyl-3-acetylpyrazolo-[1,5-a]pyridine (1.16 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=O.B.O1CCCC1.Cl.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[CH2:5][NH2:7]
Reactant: COc1cc(C)ccc1C(N)=O
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)ccc1CN
Temperature: 60 °C
Yield: 63.8 %

Procedure:
To a solution of 2-methoxy-4-methylbenzamide (14.55 g, 88.08 mmol) in dry THF (50 mL) was added dropwise Borane-tetrahydrofuran complex (1.0 M in THF, 220 mL, 2.5 eq) at 0° C. under N2 atmosphere. The reaction mixture was then heated to 60° C. overnight. The reaction was cooled to room temperature, aq.HCl (6 N, 37 mL) was added carefully and the reaction mixture was then heated at 70° C. for 2 hrs. After cooling, water was added and the resulting solution was washed with ether. The aqueous layer was basified with aq. NaOH (10 N) at 0° C. and saturated with K2CO3 then extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 8.5 g of (2-methoxy-4-methylphenyl)methanamine. (64% yield)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.C(N(CC)C1C=CC=CC=1)C.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=O>C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:24]=[C:25]([C:26]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: Cc1cccc(-c2nc3ccccc3[nH]2)c1
Temperature: 100 °C

Procedure:
The intermediate 2-(3-methylphenyl)benzimidazole was prepared by first mixing reacting 1-amino-2-nitrobenzene (8.50 g, 61.54 mmol) with toluene (180 ml) and heating to 100° C. To this mixture was then added 20 ml of N,N-diethylaniline and the reaction vessel was placed under a nitrogen atmosphere. To this solution was then added 3-methylbenzoyl chloride (24 ml, 132 mmol) and this mixture was then stirred overnight.