Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=3)[N:9]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[NH2:61][C@@H:62]1[CH2:67][CH2:66][CH2:65][N:64]([CH2:68][C:69]2[CH:76]=[CH:75][CH:74]=[CH:73][C:70]=2[C:71]#[N:72])[CH2:63]1>CN(C=O)C>[C:71]([C:70]1[CH:73]=[CH:74][CH:75]=[CH:76][C:69]=1[CH2:68][N:64]1[CH2:65][CH2:66][CH2:67][C@@H:62]([NH:61][C:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:8]=[C:7]3[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:17])[CH2:63]1)#[N:72]
Reactant: N#Cc1ccccc1CN1CCC[C@@H](N)C1
Reactant: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: N#Cc1ccccc1CN1CCC[C@@H](NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 40 °C
Reaction time: 23 h

Procedure:
To a microwave vial equipped with a stir bar was added 3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (50 mg, 0.104 mmol), HOBT (23.85 mg, 0.156 mmol), EDC (29.9 mg, 0.156 mmol), DIPEA (54.4 μl, 0.311 mmol), 2-{[(3R)-3-aminopiperidin-1-yl]methyl}benzonitrile (22.35 mg, 0.104 mmol), and DMF (1038 μl). The vial was sealed and heated to 40° C. The LCMS taken after 23 hours indicates formation of the desired product. The crude reaction mixture was filtered through a column pre-packed with celite. The material was dry loaded onto 2×10 g columns. The desired product eluted and fractions were collected and concentrated in vacuo.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:13]([CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][I:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C=O)C>C(#N)C>[I-:21].[CH2:13]([CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][N+:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][NH+:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[I-:21]
Reactant: CCCCCCCCC(CI)CCCCCC
Reactant: c1cc(-c2ccncc2)ccn1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCCCCC(CCCCCC)C[n+]1ccc(-c2cc[nH+]cc2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.6 %

Procedure:
Under a nitrogen atmosphere, to a reaction vessel, 499 mg (3.19 mmol) of 4,4′-bipyridyl, 1.496 g (4.25 mmol, 1.3 eq) of 2-hexyl-1-iododecane, 10 mL of N,N′-dimethylformamide, and 40 mL of acetonitrile were added. The whole was stirred for 30 minutes at room temperature, and subsequently refluxed at 60° C. for 2 days. The reaction mixture was allowed to reach room temperature, and then the solvent was removed by evaporation. The procedure in which the residue was dissolved in a small amount of THF, reprecipitated with hexane and the precipitate was filtered under reduced pressure, was repeated twice to give 61 mg (120 μmol) of [1-(2-hexyldecyl)-4,4′-bipyridinium]iodide as a yellow solid (yield: 4%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1.[CH2:9]([NH2:12])[CH2:10][NH2:11]>O1CCCC1.O>[N:4]1([CH2:3][CH2:2][N:11]=[CH:10][CH2:9][NH2:12])[CH:8]=[CH:7][CH:6]=[N:5]1
Reactant: NCCN
Reactant: BrCCn1cccn1
Solvent: O
Solvent: C1CCOC1
Product: NCC=NCCn1cccn1
Yield: 50 %

Procedure:
A solution of 1-(2-bromoethyl)pyrazole [6d] (12 mmol) in tetrahydrofuran was added dropwise to a solution of ethylenediamine (0.24 mol) in water. The mixture was refluxed for 4 hours. The THF was removed under vacuum and the water phase was washed with dichloromethane. After drying under vacuum resulted a yellow oil which was formulated as pz(CH2)2NH(CH2)2NH2 (1). Yield: 50%
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[ClH:1].[ClH:1].[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH2:24][CH2:23]1)[CH3:21]
Reactant: COc1ccc2cc(-c3ccccc3)nc(Cl)c2c1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1CCN(c2nc(-c3ccccc3)cc3ccc(OC)cc23)CC1
Product: Cl

Procedure:
1-Chloro-7-methoxy-3-phenylisoquinoline (0.20 g) was reacted with N-ethylpiperazine (3 ml) and potassium carbonate (0.2 g) at 120° C. for 5 hr. To the reaction solution were added ethyl acetate and water, and it was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.18 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].[Cl-].[Li+].CN(C)C=O>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1)=[O:12]
Reactant: COc1ccc(C(=O)C2(Br)CCCCC2)c(Cl)c1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)C2=CCCCC2)c(Cl)c1Cl

Procedure:
1-Bromocyclohexyl 2,3-dichloro-4-methoxyphenyl ketone (47.3 g., 0.13 mole), lithium chloride (16.5 g., 0.39 mole) and dimethylformamide (200 ml.) are heated at 90° C for 2 hours, then poured into water (1 l.) to give 36.5 g. of 1-cyclohexenyl 2,3-dichloro-4-methoxyphenyl ketone which melts at 126°-129° C. after drying at 60° C. under vacuum for 16 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14](OCC)=[O:15])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[BH4-].[Na+].O.C(Cl)Cl>C(O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][OH:15])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:22])[F:23]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 20 °C
Reaction time: 10 h
Yield: 35.4 %

Procedure:
To a solution of ethyl 2-(5-(4-chloro-3-(trifluoromethyl)phenoxy)pyridin-2-yl)acetate (2 g, 4.45 mmol) in ethanol (20 mL) was added sodium borohydride (1.683 g, 44.5 mmol). The reaction mixture was stirred at 20° C. for 10 hr. To the reaction mixture was added 50 mL of H2O and 50 mL of CH2Cl2. The organic layer was separated and dried over Na2SO4 and concentrated under reduced pressure. The crude product was added to a prep HPLC column eluting with MeCN/TFA 0.1% to provide 2-(5-(4-chloro-3-(trifluoromethyl)phenoxy)pyridin-2-yl)ethanol (500 mg, 25.5%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C@:15]3([CH3:20])[C:17]([CH3:19])([CH3:18])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:10](=[O:21])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C@:15]3([CH3:20])[C:17]([CH3:18])([CH3:19])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:10](=[O:21])[N:9]1[CH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)[nH]n1Cc1ccccc1
Reactant: Cc1nc(CCl)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1nc(Cn2c(=O)c3c(n2Cc2ccccc2)[C@@]2(C)CC[C@@H]3C2(C)C)cs1
Temperature: 110 °C
Yield: 61.5 %

Procedure:
A solution of (4R,7S)-1-benzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 49; 109 mg, 0.38 mmol), tetrabutylammonium iodide (147 mg, 0.39 mmol) and 4-(chloromethyl)-2-methylthiazole (Maybridge plc, Tintagel, Cornwall, UK; 60 mg, 0.40 mmol) in dimethylformamide (3.9 mL) was heated at 100° C. for 24 h. A second portion of 4-(chloromethyl)-2-methylthiazole (120 mg, 0.81 mmol) was added and the mixture was heated at 110° C. overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with saturated aqueous sodium thiosulfate (150 mL), saturated aqueous sodium hydrogen carbonate (150 mL) and brine (150 mL), dried (sodium sulfate), filtered, evaporated and purified using a Biotage 40S system, eluting with 2% methanol/dichloromethane, to give (4R,7S)-1-benzyl-7,8,8-trimethyl-2-(2-methyl-thiazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (92 mg, 61%) as a reddish-brown semi-solid. APCI(+)-MS (M+H) 394.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:7]=[C:8]([NH:10]C(OCC2C=CC=CC=2)=O)[CH:9]=1)=[O:4].CO>[Pd].O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(NC(=O)OCc2ccccc2)nn1Cc1ccc(OC)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)nn1Cc1ccc(OC)cc1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
In a round bottom flask, 5-benzyloxycarbonylamino-2-(4-methoxy-benzyl)-2H-pyrazole-3-carboxylic acid methyl ester (108, 2.3 g, 5.8 mmol) was combined with 30 mL of methanol and 10 mL of tetrahydrofuran under nitrogen and 10% palladium on carbon (0.23 g, 13.0 mmol) was added. The reaction was stirred under hydrogen at 1 atmosphere for 2 hours. The reaction was filtered and the filtrate concentrated under vacuum to provide the desired compound (109, 1.4 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[C:34]([CH:35]=O)=[C:33]([NH:37]C(=O)OC(C)(C)C)[CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.O>[Cl:28][C:29]1[N:30]=[CH:31][CH:32]=[C:33]2[C:34]=1[CH:35]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:17][CH2:18][CH2:19]3)=[CH:12][CH:11]=1)=[N:37]2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CCC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a round bottom flask was added tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (1-3) (2.7 g, 6.1 mmol), tert-butyl (2-chloro-3-formylpyridin-4-yl)carbamate (1-4) (1.6 g, 6.1 mmol), potassium carbonate (5.0 g, 6.0 mmol), and DMF (20 mL). The reaction mixture was heated to 80° C. while stirring in a hot oil bath under an atmosphere of nitrogen for 15 hours. Then the reaction mixture was warmed to 120° C. for 1 hour. The reaction mixture was permitted to cool to room temperature, added water, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (5-50% EtOAc/5% DCM/Hexane) to give tert-butyl {1-[4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-5) as an off-white solid. HRMS (M+H)+: observed=486.1954, calculated=486.1943.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([F:22])[CH:13]=2)[CH:5]=1.[F:24][CH2:25][CH:26](O)[CH2:27][F:28].[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1>>[F:24][CH2:25][CH:26]([CH2:27][F:28])[O:10][C:8]1[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[C:14]([F:22])[CH:13]=2)[CH:5]=[C:4]([CH:9]=1)[C:3]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:23]
Reactant: Cn1ccc(N)n1
Reactant: OC(CF)CF
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(S(C)(=O)=O)c(F)c2)c1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)c(F)c3)cc(OC(CF)CF)c2)n1

Procedure:
The compound of Production Example 166 was obtained as a colorless amorphous substance using 3-(3-fluoro-4-methanesulfonylphenoxy)-5-hydroxy-benzoic acid methyl ester, 1,3-difluoro-2-propanol and 3-amino-1-methyl-1H-pyrazole obtained in the same manner as Production Example 42, by the same method as in Production Example 2, a corresponding method, or a combination thereof with an ordinary method.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[C:14]([O:19][CH3:20])(=[O:18])/[CH:15]=[CH:16]/[CH3:17].CC(C)([O-])C.[K+]>>[CH3:17][C:16]1[C:15]([C:14]([O:19][CH3:20])=[O:18])=[CH:10][NH:11][CH:12]=1
Reactant: C/C=C/C(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)c1c[nH]cc1C

Procedure:
By a similar operation as in Reference Example 19 and using p-toluenesulfonylmethyl isocyanide (94.6 g), methyl crotonate (48.5 g) and potassium tert-butoxide (76.7 g), the title compound was obtained as a pale-yellow solid (yield 16.8 g, 25%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][C:13]([OH:15])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][CH:7]=[N:8]3)[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1c(F)ccc2ncccc12
Product: O=C(Cc1c(F)ccc2ncccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroquinolin-5-yl)acetamide was prepared from 2-(6-fluoroquinolin-5-yl)acetic acid (42 mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min)=2.499, method [7], MS (ESI) 432.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.99 (dd, J=4.2, 1.1 Hz, 1H), 8.86 (d, J=7.9 Hz, 1H), 8.23 (dd, J=8.9, 4.5 Hz, 1H), 8.08 (s, 1H), 7.85 (dd, J=9.4, 9.2 Hz, 1H), 7.81 (dd, J=9.2, 4.5 Hz, 1H), 7.07 (s, 1H), 4.48 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:20][CH2:21][CH2:22][OH:23])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([O-])(=[O:40])=[O:39])=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:20][CH2:21][CH2:22][O:23][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=3)(=[O:40])=[O:39])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCO)(c2ccc(Br)cc2)C1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOC2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ambient solution of Example 54C (0.450 g, 1.17 mmol), triethylamine (0.178 mL, 1.28 mmol), and 4-dimethylaminopyridine (0.005 g, 0.041 mmol) in dichloromethane (3 mL) was added p-toluenesulfonate chloride (0.224 g, 1.17 mmol). The reaction was stirred at room temperature for 8 h and was then partitioned between water (10 mL) and dimethyl ether (10 mL). The layers were separated, and the aqueous was extracted with additional diethyl ether (2×10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (10% ethyl acetate in hexane to 25% ethyl acetate in hexane) to give the title product. MS (ESI) m/z 541[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].Cl.C(=O)([O-])[O-].[K+].[K+].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20](=[O:19])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][NH:9]1
Reactant: NNc1ccccc1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2ccccc2Cl)c1=O
Yield: 77.7 %

Procedure:
In the same manner as in Reference Example 63 and using (2-chlorophenyl)hydrazine•hydrochloride (5 g, 28 mmol), water (100 mL), potassium carbonate (8.5 g, 62 mmol) and diethyl ethoxymethylenemalonate (7.3 g, 34 mmol) as starting materials, the title compound (5.8 g, 78%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][NH2:21])[CH2:14]1.C([N:24](CC)CC)C.[O:29]=[C:30]1[NH:35][C:34]2C=[C:37]([S:40](Cl)(=[O:42])=[O:41])[CH:38]=[CH:39][C:33]=2[S:32][CH2:31]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][NH:21][S:40]([C:37]2[CH:38]=[CH:39][C:33]3[S:32][CH2:31][C:30](=[O:29])[NH:35][C:34]=3[N:24]=2)(=[O:42])=[O:41])[CH2:14]1
Reactant: COc1ccc2nccc(N3CCC(NCCN)C3)c2n1
Reactant: CCN(CC)CC
Reactant: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2nccc(N3CCC(NCCNS(=O)(=O)c4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 0.75 h
Yield: 46 %

Procedure:
N1-[1-(6-Methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-yl]-ethane-1,2-diamine (213 mg, 0.74 mmol) (from Example 2c) was dissolved in DCM (2 mL) with triethylamine (0.31 mL, 2.2 mmol) and cooled in an ice bath. The cooled solution was treated with 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonyl chloride and stirred 45 minutes. The reaction mixture was diluted with chloroform and poured into saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 0-10% MeOH in CDCl3 (1% NH4OH) to afford the title compound as a white solid (174 mg, 46%): LC/MS m/z 515 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 8.28 (d, J=5 Hz, 1H), 8.04 (d, J=9 Hz, 1H), 7.43-7.36 (m, 2H), 6.97 (d, J=9 Hz, 1H), 6.30 (d, J=5 Hz, 1H), 4.03 (m, 1H), 3.94 (s, 3H), 3.85 (m, 1H), 3.71 (m, 1H), 3.43 (s, 2H), 3.38 (m, 1H), 3.06 (m, 2H), 2.82 (m, 2H), 2.10 (m, 1H), 1.85 (m, 1H), 1.70-1.60 (m, 1H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][C:11]([O:15][CH3:16])(C)[CH:12]=[O:13].[CH2:17](O)C(C)C>>[CH3:5][N:4]([CH3:6])/[CH:3]=[CH:17]/[C:12](=[O:13])[CH:11]([O:15][CH3:16])[O:10][CH3:9]
Reactant: COC(C)(C=O)OC
Reactant: CC(C)CO
Reactant: COC(OC)N(C)C
Product: COC(OC)C(=O)/C=C/N(C)C
Temperature: 100 °C
Yield: 48 %

Procedure:
A mixture of N,N-dimethylformamide dimethylacetal (86.0 g, 584 mmol) and methylglyoxal 1,1-dimethylacetal (85.6 g, 724 mmol) in isobutanol (500 mL) was heated at 100° C. overnight. The mixture was then cooled and evaporated. Purification by distillation afforded the title product (49.9 g, 48%) as an orange liquid. Bp 123-124° C. at 0.9 mbar. MS: m/e=174.4 [M+H]|.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]2[C:11]([NH2:13])=O)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]2[CH2:11][NH2:13])[CH2:2][CH2:3]1.[NH3:5]
Reactant: NC(=O)[C@H]1CCCCN1CC1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: N
Product: NC[C@H]1CCCCN1CC1CC1

Procedure:
The title compound was prepared by a similar method to preparation 60 from (2R)-1-(cyclopropylmethyl)-2-piperidinecarboxamide [see preparation 69] and lithium aluminum hydride. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:0.1) as the eluant, to afford the product as a yellow oil, (71%).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.CO[C:17](=[O:27])[CH2:18][NH:19][C:20]([C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1)=[O:21]>CO>[C:20]1(=[O:21])[NH:19][CH2:18][C:17](=[O:27])[N:23]2[CH2:24][CH2:25][CH2:26][C@@H:22]12
Reactant: COC(=O)CNC(=O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC(=O)N2CCC[C@@H]12
Temperature: 25 °C
Yield: 34.4 %

Procedure:
Triethylamine (75 ml, 540 mmol) was added to a solution of the crude trifluoroacetic acid salt of [((S)-pyrrolidine-2-carbonyl)amino]acetic acid methyl ester (15.4 g), which was isolated in the previous step, in methanol (300 ml). The reaction mixture was heated to reflux for 16 hours. It was cooled to room temperature. The solvent was removed in vacuo. The residue was suspended in 2-propanol (150 ml). The precipitation was isolated and dried in vacuo to give 4.38 g of (S)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1CNc1ccc(O)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: CCCCc1oc2ccccc2c1CNc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 68.2 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[(2-butyl-benzofuran-3-ylmethyl)-amino]-phenol (0.500 g, 1.69 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.401 g, 1.69 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with 25% EtOAc/hexane gave 0.571 g (85%) of the title compound as a dark yellow solid, mp 75-77° C. 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.31 (sextet, 2H), 1.60 (quintet, 2H), 2.80 (t, 2H), 4.23 (s, 2H), 6.54 (d, 2H), 6.72 (d, 2H), 7.14-7.22 (m, 2H), 7.26-7.30 (m, 2H), 7.45 (dd, 1H), 7.58 (dd, 1H), 7.95 (d, 1H). IR (KBr) 3400, 2950, 1600, 1510 and 1380 cm−1. mass spectrum (−ESI) m/z 494 (M−H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:19]=[CH:18][C:17]2=[C:20]3[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]3[C:11](=[O:25])[C:12]1[C:13]3[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=3[O:15][C:16]=12.[CH2:26]([NH2:28])[CH3:27].[CH2:29](O)[CH3:30]>>[CH2:26]([N:28]([CH2:29][CH3:30])[CH2:2][CH2:3][O:4][C:5]1[CH:19]=[CH:18][C:17]2=[C:20]3[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]3[C:11](=[O:25])[C:12]1[C:13]3[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=3[O:15][C:16]=12)[CH3:27]
Reactant: CCO
Reactant: O=C1c2c(oc3ccccc23)-c2ccc(OCCBr)c3cccc1c23
Reactant: CCN
Product: CCN(CC)CCOc1ccc2c3c(cccc13)C(=O)c1c-2oc2ccccc12

Procedure:
A suspension of 4.4. g. (11.2 mmol.) of 3-(2-bromoethoxy)-7-oxo-7H-benzo[b]phenaleno[2,1-d]furan and 10 ml. of ethylamine in 250 ml. of absolute ethanol was refluxed for 4 days. The reaction mixture was filtered while hot, the filtrate was evaporated to dryness and the semi-solid residue was dissolved in methylene chloride. The methylene chloride solution was extracted twice with dilute sodium hydroxide solution and once with water, dried (MgSO4) and evaporated to dryness to give a residue which was crystallized from hexane to give the title compound, m.p. 115°-118°.