Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].C(O[CH2:26][CH:27]([N+:30]([O-:32])=[O:31])[CH2:28][CH3:29])(=O)C>N1C=CC=CC=1>[N+:30]([CH:27]([CH2:28][CH3:29])[CH2:26][N:5]1[C:4](=[O:21])[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6]1)([O-:32])=[O:31]
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Reactant: CCC(COC(C)=O)[N+](=O)[O-]
Solvent: c1ccncc1
Product: CCC(Cn1nc(-c2ccccc2)c(-c2ccccc2)c(C#N)c1=O)[N+](=O)[O-]
Yield: 38.2 %

Procedure:
4.0 grams (0.014 mole) of the product of Example 1 was reacted with 2.37 grams (0.014 mole) of 2-nitrobutyl acetate in 100 mls of dry pyridine. This solution was heated to reflux for 1 hour, cooled and the solvent distilled at reduced pressure. The residual solid was recrystallized from methyl alcohol to give 2.0 grams (37% yield) of a white-yellow solid melting at 154°-155° C. The infrared spectrum showed the C-C band at 3.5μ, the nitrile band at 4.5μ, and the amide carbonyl band at 6.0μ.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[C:40]([NH:42][C:43](=[O:45])[CH3:44])[CH:39]=[CH:38][N:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[C:40]([NH:42][C:43](=[O:45])[CH3:44])[CH:39]=[CH:38][N:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(=O)Nc1ccnc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccnc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 43 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-(2-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-4-pyridyl)acetamide (0.590 g) and pyridine hydrochloride (190 mg), the title compound (150 mg) was obtained as colorless powder crystals.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:42]1[N:43]=[C:44]([NH:47][CH:48]=[O:49])[S:45][CH:46]=1)[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6].ClC1C=CC=C(C(OO)=[O:58])C=1>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:42]1[N:43]=[C:44]([NH:47][CH:48]=[O:49])[S:45][CH:46]=1)[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[O:18])[CH2:13][S:14](=[O:58])[C@H:9]12)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)n3ccnc3)CS[C@H]12)c1csc(NC=O)n1
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)n3ccnc3)CS(=O)[C@H]12)c1csc(NC=O)n1
Yield: 79.7 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-imidazolyl)carbonyloxymethyl-3-cephem-4-carboxylate (syn isomer) (13.5 g) in tetrahydrofuran (200 ml) was added m-chloroperbenzoic acid (5.8 g) with stirring under ice-cooling, followed by stirring for an hour at 5° C. The reaction mixture was evaporated and the residue was pulverized in diethyl ether, collected by filtration, washed with ethyl acetate and diethyl ether and then dried to give benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-imidazolyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (11.0 g).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9][CH2:8]1.C(N(CC)CC)C>ClCCl>[O:9]1[C:10]2([CH2:15][CH2:14][N:13]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:12][CH2:11]2)[O:16][CH2:7][CH2:8]1
Reactant: O=C(Cl)C1CC1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC2(CC1)OCCO2
Reaction time: 8 h

Procedure:
A solution of 10.4 g. of cyclopropanecarbonyl chloride in 150 ml. of dichloromethane is rapidly added to a solution of 12.5 g. of 4-piperidone ethylene acetal (1,4-dioxa-8-azaspiro[4.5]decane) and 20 g. of triethylamine in 200 ml. of dichloromethane, causing the solution to reflux. Heating to reflux with stirring is continued overnight; the mixture is cooled and the precipitated triethylammonium chloride filtered off. The mother liquor is concentrated to about half volume, washed with water, dried over anhydrous potassium carbonate, and stripped to dryness. The residual oil quickly solidifies, and on crystallization from 300 ml. hexane yields cyclopropyl 1,4-dioxa-8-azaspiro[4.5]dec-8-yl ketone, m.p. 72°-74°, as white needles. Reduction of 14.0 g. of this compound in 60 ml. freshly chromatographed, peroxide-free ether by dropwise addition to a suspension of 2.5 g. of lithium aluminum hydride in similarly treated ether, followed by three hours of refluxing, yields 8-(cyclopropylmethyl)-1,4-dioxa-8azaspiro[4.5]decane as a colorless oil. Hydrolysis of this ethylene acetal by refluxing in 2N hydrochloric acid, followed by basification with 50% sodium hydroxide, extraction into ether, drying of the extrct, and stripping off the solvent, yields a crude product which distills at 111°-122°/16 mm. to give 1-(cyclopropylmethyl)-4-piperidone, shown by gas-liquid chromatography to be 95-99% pure.
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:18])[CH2:12][NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:5][C:4]=1Br>>[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:11]([OH:18])[CH2:12][NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: N#Cc1cc(C(O)CNC2CCC2)cc(Br)c1N
Agent: Br
Product: N#Cc1cc(C(O)CNC2CCC2)ccc1N

Procedure:
m.p. of the hydrobromide: >193° C. (decomp.), was prepared from 1-(4'-amino-3'-bromo-5'-cyano-phenyl)-2-cyclobutylamino-ethanol analogous to Example 51.
Reaction SMILES: [OH-].[K+].Cl.[CH2:4]([N:6]([CH2:34][CH3:35])[CH2:7][CH:8]([OH:33])[CH2:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH:27][CH2:28][CH:29]([OH:32])[CH2:30]Cl)=[CH:13][CH:12]=1)[CH3:5]>CO>[CH2:4]([N:6]([CH2:34][CH3:35])[CH2:7][CH:8]([OH:33])[CH2:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH:27][CH2:28][CH:29]2[O:32][CH2:30]2)=[CH:13][CH:12]=1)[CH3:5]
Reactant: CCN(CC)CC(O)CNc1ccc(NCC(O)CCl)c2c1C(=O)c1ccccc1C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CC(O)CNc1ccc(NCC2CO2)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Potassium hydroxide (0.3 g, 5.36 mmole) was added to a solution of 1-(3-diethylamino-2-hydroxypropylamino)-4-(3-chloro-2-hydroxypropylamino)-9, 10-anthracenedione hydrochloride salt (1 g, 1.78 mmole), the compound of Example 3, in methanol. The mixture was stirred at room temperature for 48 hours. Solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, chloroform with a methanol gradient up to a ratio of 10:1) to give the title product 1-(3-diethylamino-2-hydroxypropylamino)-4-(2, 3-epoxypropylamino)-9, 10-anthracenedione which is compound 1b-1 of Table 1 (391 mg, 52%), mp 98° C.: NMR (CDCl3) δ1.06 (t, J=7.1 Hz, 6H, CH3), 2.62 (m, 7H, CH2), 2.87 (m, 1H, CH2), 3.27 (m, 1H, CH2), 3.49 (m, 2H, CH2), 3.59 (m, 1H CH2), 3.77 (m, 1H, CH), 3.96 (m, 1H, CH), 7.35 (s, 2H, Ar (2, 3)), 7.71 (m, 2H, Ar (6, 7)), 8.35 (m, 2H, Ar (5, 8)), 10.80 (b, 1H, NH), 10.92 (b, 1H, NH); Anal. Calcd for C24H29N3O4 : C, 68.1; H, 6.90; N, 9.92. Found: C, 67.86; H, 6.96; N, 9.85.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[C:12]=1[CH:13]=[O:14]>CO>[CH3:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[C:12]=1[CH2:13][OH:14]
Reactant: Cc1nc2ccccn2c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2ccccn2c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of sodium borohydride (531 mg, 14.0 mmol) in methanol (30 mL) was added a solution of 2-methylimidazo[1,2-a]pyridine-3-carbaldehyde (1.5 g, 9.4 mmol) in methanol (5 mL) at 0° C. The mixture was stirred for 2 hours at room temperature. The solvent was evaporated, water was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, {2-methylimidazo[1,2-a]pyridin-3-yl}methanol was obtained (914 mg, 59% yield) and used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6): δ 2.31 (s, 3H), 4.74 (d, J=5.4 Hz, 2H), 5.06 (t, J=5.4 Hz, 1H), 6.86 (dt, J=6.8 Hz, J=1.3 Hz, 1H), 7.16-7.21 (m, 1H), 7.42 (td, J=9.0 Hz, J=1.2 Hz, 1H), 8.28 (td, J=6.8 Hz, J=1.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][C:6]2([CH3:14])[CH3:13].[CH:15](O)=[O:16].Cl.CN(C)CCCN=C=NCC>ClCCl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH:15]=[O:16])[CH2:7][C:6]2([CH3:14])[CH3:13]
Reactant: O=CO
Reactant: COc1ccc2c(c1)C(C)(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(C)(C)CN(C=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (Intermediate 18, 3.2 g, 16.7 mmol) in anhydrous dichloromethane (40 mL) was treated with formic acid (1 mL, 26.5 mmol) followed 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.9 g, 20.34 mmol) and the resulting solution was stirred at ambient temperature overnight. It was then diluted with chloroform and washed with water (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as pale brown viscous oil (3.26 g, 90%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:12][CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4]1.[Li]CCCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>C1COCC1>[CH3:1][O:2][CH:3]1[CH:12]([B:18]([OH:23])[OH:19])[CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COC1CCc2ccccc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1Cc2ccccc2CC1B(O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A −78° C. solution of 10.0 g (61.6 mmol) of 6-methoxy-5,6,7,8-tetrahydronaphthalene in 75 mL of THF was treated in a dropwise manner with 42.0 mL (67.2 mmol) of 1.6 M n-BuLi in hexanes. The mixture was stirred for 1 hr and was treated with 14.8 mL (64.1 mmol) of triisopropyl borate. The reaction was allowed to warm slowly to 0° C. and was stirred at this temperature for 0.5 hr. The reaction was quenched by the careful addition of 120 mL of aq 1N HCl. The layers were separated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford a white solid which was used in part B without further purification.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[C:18]([C:21]1[C:29](=[O:30])[N:28]2[C:24]([S:25][C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=32)=[N:23][CH:22]=1)([OH:20])=O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>CN(C)C=O>[NH:37]1[C:36]([NH:35][C:18]([C:21]2[C:29](=[O:30])[N:28]3[C:24]([S:25][C:26]4[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=43)=[N:23][CH:22]=2)=[O:20])=[N:40][N:39]=[N:38]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cnc2sc3ccccc3n2c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1cnc2sc3ccccc3n2c1=O

Procedure:
To a solution of 360 mg. of 1,1'-carbonyldiimidazole in 6 ml. of dry tetrahydrofuran at 140° C. is added dropwise 500 mg. of 3-carboxy-4-oxo-4H-pyrimido[2,1-b]benzothiazole in 6 ml. of dry dimethylformamide. After heating for 3 hrs., 186 mg. of 5-aminotetrazole is added, and the heating maintained for an additional 15 min. The reaction mixture is cooled and the precipitated product filtered. Recrystallization from dimethylformamide gives 200 mg. of the desired product, m.p. 330°-332° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1>>[NH2:37][C:32]1[CH:31]=[C:30]([F:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: Nc1ccc(F)cc1N
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Nc5ccc(F)cc5N)cccc4c3)c2cc1OC
Yield: 80.9 %

Procedure:
The title compound (39.1 mg, 81% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid (37.5 mg, 0.1 mmol) and 4-fluoro-o-phenylenediamine (15.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.93 (s, 3H, —OCH3), 3.95 (s, 3H, —OCH3), 5.31 (s, 2H, benzene-NH2), 6.40 (s, 1H, Ar—H), 6.55-6.59 (m, 2H, Ar—H), 7.30 (d, J=7.6 Hz, 1H, Ar—H), 7.42 (s, 1H, Ar—H), 7.54-7.57 (m, 2H, Ar—H), 7.64 (t, J=8.0 Hz, 1H, Ar—H), 7.89-7.91 (m, 2H, Ar—H), 8.07 (d, J=8.0 Hz, 1H, Ar—H), 8.42 (d, J=9.2 Hz, 1H, Ar—H), 8.49 (d, J=5.2 Hz, 1H, Ar—H), 9.79 (s, 1H, benzene-NH). LC-MS (m/z) 484 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([S:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1.[NH3:22]>CO>[CH3:21][C:4]1[CH:3]=[C:2]([NH2:22])[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([S:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1cccs1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1cccs1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-5-methyl-2-methylsulphanyl-3-(thiophene-2-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(thiophene-2-sulphonyl)-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:22]([C:19]4[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=4)=[CH:23][C:24](=[O:25])[NH:14][C:5]=23)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2c(C)n[nH]c2N)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(C)nn3c(-c4ccc(F)cc4)cc(=O)[nH]c23)cc1
Temperature: 25 °C

Procedure:
3-Methyl-4-(4-methylphenyl)-1H-pyrazol-5-amine and ethyl 3-(4-fluorophenyl)-3-oxopropanoate are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]([NH:11][CH2:12][CH:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21](F)=[C:20]([F:25])[CH:19]=2)[CH2:14]1)(=[O:10])[CH3:9]>CN(C)C=O.C(OCC)(=O)C>[F:25][C:20]1[CH:19]=[C:18]([C:15]2[CH2:14][CH:13]([CH2:12][NH:11][C:8](=[O:10])[CH3:9])[O:17][N:16]=2)[CH:23]=[CH:22][C:21]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)NCC1CC(c2ccc(F)c(F)c2)=NO1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NCC1CC(c2ccc(-n3ccnc3)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
Imidazole (225 mg) is dissolved in 5 ml dimethylformamide in a 25 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated with 60% sodium hydride (132 mg), and the mixture is stirred 20 minutes at room temperature. The solution is treated with (-)-5-(acetamidomethyl)-3-(3,4-difluorophenyl)-isoxazoline (Step 1, Example 11) (763 mg), and the reaction is stirred 6 hours at 65° C. The reaction is cooled, is diluted with 25 ml ethyl acetate, and is washed with 4×25 ml 50% saturated 1:1 sodium chloride/sodium bicarbonate. The organics are dried over anhydrous magnesium sulfate and are concentrated in vacuo to a white solid. The crude material is chromatographed over 25 g silica gel (230-400 mesh), eluting with 4% methanol/dichloromethane while collecting 5 ml fractions. Fractions 33-69 are combined and concentrated to give 256 mg of a white solid which is washed with ethyl acetate to afford 227 mg (25%) of the title compound as a white solid, mp 155-156° C, [α]25D -76° (c 0.30).
Reaction SMILES: [NH2:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]([O:28]C)=[O:27])[CH2:15][N:14]3[C:30]=2[CH:31]=1)=[O:7])(=[O:4])=[O:3].CO.[OH-].[Na+].Cl>CO.O>[NH2:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[CH2:15][N:14]3[C:30]=2[CH:31]=1)=[O:7])(=[O:3])=[O:4]
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(N)(=O)=O)cc3n2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(N)(=O)=O)cc21
Temperature: 60 °C
Yield: 93.5 %

Procedure:
Methyl 10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate (725 mg, 1.39 mmol) was dissolved into MeOH//THF (1:1, 16 mL) and treated with 1M aqueous NaOH (3 mL). The reaction mixture was stirred and heated at 60° C. for 0.5 h and cooled to rt. The reaction solution was diluted with MeOH/H2O (2:1, 15 mL), neutralized with 1M aqueous HCl (3 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O and dried under vacuum to yield 10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (650 g, 1.3 mmol, 92%) as a bright yellow solid which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 1.16-2.22 (m, 10H), 2.82-2.96 (m, 1H), 3.94 (s, 3H), 4.07-4.29 (m, 1H), 5.57-5.80 (m, 1H), 7.14-7.23 (m, 2H), 7.55-7.63 (m, 2H), 7.88-7.94 (m 2H), 8.18 (s, 1H). LCMS: m/e 510 (M+H)+, ret time 2.85 min, column B, 4 minute gradient.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:34]=[CH:35][CH:36]=1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[N:21]=[CH:22][C:23]([NH:26]C(=O)OC(C)(C)C)=[N:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:26][C:23]1[CH:22]=[N:21][C:20]([C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:10]3[CH:9]=[C:8]([CH:36]=[CH:35][CH:34]=3)[C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:14]2)=[O:19])=[CH:25][N:24]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cnc(NC(=O)OC(C)(C)C)cn3)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cnc(N)cn3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A mixture of tert-butyl 5-(1-(3-(tert-butylcarbamoyl)benzyl)piperazine-4-carbonyl)pyrazin-2-ylcarbamate (Example 30;120 mg, 0.242 mmol), dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 3 hours and was then concentrated under vacuum. The residue was triturated with diethyl ether and then gravity filtered over fluted paper. The collected solid was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to afford the title compound (89 mg). MS (ESI) m/z 397.2 [M-+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][CH2:13][N:14]([C:21]([O:23]C(C)(C)C)=[O:22])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=1>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][CH2:13][N:14]([C:21]([O:23][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:22])[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:5]=1
Reactant: COC(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc(OCCN(C(=O)OCc2ccccc2)c2ccncc2)c1
Reaction time: 20 h
Yield: 62.2 %

Procedure:
A solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid methyl ester (0.950 g) in dichloromethane (16 ml) and trifluoroacetic acid (4 ml) was stored at room temperature for 1 h. The solution was concentrated in vacuo and residual trifluoroacetic acid removed by co-evaporation with further dichloromethane. The residue was dissolved in dichloromethane (20 ml) and the solution stirred with saturated aqueous sodium bicarbonate (25 ml). Benzyl chloroformate (0.394 ml) was added to the bi-phasic mixture and stirring continued for 20 h. The aqueous layer was removed and the organic layer washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (3:1 v/v), to give the title compound as a colourless gum (0.32 g).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:34]([OH:35])=[CH:33][CH:32]=[CH:31][C:8]=1[O:9][CH2:10][CH:11]([OH:30])[CH2:12][O:13][C:14]1[C:19]2[C:20](=[O:29])[CH:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:6].C(O)C.Cl.O>C(Cl)(Cl)Cl>[O:6]=[C:5]1[C:7]2[C:8]([O:9][CH2:10][CH:11]([OH:30])[CH2:12][O:13][C:14]3[C:19]4[C:20](=[O:29])[CH:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:23][C:18]=4[CH:17]=[CH:16][CH:15]=3)=[CH:31][CH:32]=[CH:33][C:34]=2[O:35][CH:3]=[CH:4]1
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc(O)c3C(=O)C=CN(C)C)cccc2o1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc4occc(=O)c34)cccc2o1

Procedure:
0.200 parts of ethyl 5-(3-[2-{3-dimethylaminoacryloyl}-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate were refluxed for 16 hours in 15.8 parts of ethanol containing 1 part of concentrated hydrochloric acid. The solution was poured into a stirred mixture of 10 parts of water and 73 parts of chloroform and the organic extract separated, and washed with 5% sodium bicarbonate solution and water. Evaporation of the chloroform gave a residue which was chromatographed on silica gel, eluting with 1:1 chloroform/ethyl acetate. The product obtained from chromatography was crystallised from ethanol to give 0.027 parts of ethyl 5-(3-[4-oxo-4H-1-benzopyran-5-yloxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate, m.pt. 154°-158°.