Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[OH:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[N:37]1([CH2:43][CH2:44]O)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:44][CH2:43][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: OCCN1CCOCC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCCN1CCOCC1
Yield: 42.8 %

Procedure:
A solution of (2S)-(5-bromo-2-hydroxy-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (25 mg, 46 μmol, obtained by following similar procedure described for example 34), 2-morpholin-4-yl-ethanol (1.5 eq., 8.3 μL, 69 μmol) and triphenylphosphine (1.5 eq., 18 mg, 69 μmol) in anhydrous THF (1 mL) was treated with DIAD (1.5 eq., 13.5 μl, 69 μmol) as described in Procedure I. Flash column chromatography (4:1 hexanes:EtOAc) provided 13 mg of the title compound. LCMS for C35H35BrN2O6: 659, 661.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:22][CH3:23])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:21]=[CH:20][N:19]([CH2:22][CH3:23])[N:18]=2)[N:3]=1
Reactant: CCn1ccc(CCl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To a suspension of 3-bromo-4-nitro-1H-indazole (Preparation B; 8.51 g, 35.2 mmol) in DMF (60 mL) was added 3-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride (6.37 g, 35.2 mmol) and K2CO3 (14.6 g, 106 mmol). The reaction mixture was stirred for 16 hours. Most of DMF was removed under reduced pressure. The remaining residue was diluted with EtOAc (300 mL) and washed with H2O. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/hexanes 1:5) to provide the product (9.26 g).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:23]3[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=3[C:25]([OH:27])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:35]1C=CC=CC=1.[OH-].[NH4+]>C(#N)C.O>[C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:23]3[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=3[C:25]([NH2:35])=[O:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: CCOC(=O)N(CCCCN1CC=C(c2ccccc2)CC1)c1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N(CCCCN1CC=C(c2ccccc2)CC1)c1cc([N+](=O)[O-])ccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
A mixture of 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzoic acid (1.53 g), N,N'-disuccinimidoyl carbonate (924 mg) and pyridine (285 mg) in dry acetonitrile (20 ml) was stirred for 3 hours at room temperature. Then, to the mixture was added 28% ammonium hydroxide (1.4 ml) on an ice-bath. After 1 hour, the reaction mixture was diluted with water, and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (30 g). Elution with a mixed solvent of chloroform and methanol (50:1 V/V) gave 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzamide (600 mg) as caramel.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]3[C:29]#[N:30])=[CH:18][CH:17]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]3[C:29]3[NH:37][N:36]=[N:35][N:30]=3)=[CH:18][CH:17]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)c(Cl)c2C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)c(Cl)c2-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 22 h
Yield: 95.9 %

Procedure:
A mixture of 2-butyl-3-[4-(3,4-dichloro-2-cyano-1-pyrrolyl)benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (490 mg) and trimethyltin azide (690 mg) in xylene (5 ml) was stirred at 120° C. for 22 hours. After cooled to ambient temperature, the mixture was treated with aqueous 1N sodium hydroxide (10 ml) for 4 hours. The suspension was filtered. The filtrate was washed with diisopropyl ether, adjusted to pH 4 with aqueous 1N-hydrochloric acid, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by methanol/dichloromethane=1/8) to give 2-butyl-3-[4-[3,4-dichloro-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (516 mg) as an amorphous solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:14]=[C:15]1[CH:19]([CH2:20]OS(C)(=O)=O)[CH2:18][CH2:17][N:16]1[C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]([F:46])([F:45])[F:44])[NH:32][C:33]2=[O:36])=[CH:28][CH:27]=1.[Cl-].[NH4+]>C1COCC1>[N:1]1([CH2:20][CH:19]2[CH2:18][CH2:17][N:16]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]([F:46])([F:45])[F:44])[NH:32][C:33]4=[O:36])=[CH:28][CH:27]=3)[C:15]2=[O:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCC1CCN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C1=O
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C(CN2CCOCC2)CCN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Yield: 21.9 %

Procedure:
Morpholine (0.024 ml, 0.29 mmol) and triethylamine (0.040 ml, 0.29 mmol) were added to a THF solution (1 ml) that contained the obtained methanesulfonic acid 2-oxo-1-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]-pyrrolidin-3-ylmethyl ester (14 mg, 0.029 mmol). The obtained mixture was heated to reflux for 16 hours. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=100:1->30:1), so as to obtain 7-(3-morpholin-4-ylmethyl-2-oxo-pyrrolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (3 mg, 22%) in the form of a colorless oil substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[O:7])[CH2:5][CH2:4]1.[H-].[Na+].[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>C1COCC1>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH2:2][C:3]1([C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[O:7])[CH2:4][CH2:5]1
Reactant: CCCNC(=O)C1(CO)CC1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)C1(COc2cccc(N)c2C#N)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A solution of 1-(hydroxymethyl)-N-propylcyclopropanecarboxamide (Example 198c) (0.67 g, 4.25 mmol) in anhydrous THF (10 mL) was treated with NaH (0.17 g, 4.25 mmol, 60% suspension in mineral oil) at 0° C., under a nitrogen atmosphere. The obtained mixture was stirred at 0° C. for 10 min and at rt over 30 min. Then, a solution of 2-amino-6-fluorobenzonitrile (0.53 g, 3.86 mmol) in THF (5.0 mL) was added and the obtained mixture was heated at reflux overnight. The cold mixture was quenched with saturated aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (3×50 mL). The combined extract was washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel using gradient hexanes→hexanes/EtOAc (4:6), to give 0.75 g (71%) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.51 (t, J=6.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.34 (d, J=8.4 Hz, 1H), 6.19 (d, J=8.4 Hz, 1H), 5.97 (broad s, 2H), 4.13 (s, 2H), 3.04 (q, J=6.4 Hz, 2H), 1.43 (hex, J=6.8 Hz, 2H), 1.05-1.11 (m, 2H), 0.78-0.86 (m, 5H).
Reaction SMILES: [CH:1]1C=CC2NC=C(CCO)C=2C=1.[Li].[H-].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[C:32](=O)[C:33]([O:35][CH2:36][CH3:37])=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]1[C:36]([CH3:37])([CH3:1])[O:35][CH2:33][CH2:32][C:26]2=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [H-]
Agent: [Li]
Solvent: CC(C)=O
Product: CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21

Procedure:
5-Benzyloxy-3-tryptophol (II; R2, R3, R4 and R5 = H, R6 = 5-benzyloxy and X1 = OH), m.p. 93° - 95° C., is prepared by lithium aluinum hydride reduction of ethyl 5-benzyloxy-3-indoleglyoxalate (British Patent 778,823) according to the procedure of Example 309. Subsequent treatment of 5-benzyloxy-3-tryptophol with the ketone, acetone, according to the procedure of Example 785 affords 6-benzyloxy-1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (VIIl R1M CH3), nmr (CDCl3) δ1.53 (6H), 2.73 (t, 2H), 4.03 (t, 2H), 5.10 (2H), 6.67 - 7.83 (9H). The latter compound is then N-alkylated with the organic halide, dimethylaminoethyl chloride, according to the procedure of Example 838 to afford 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, which on treatment with hydrochloric acid gives the corresponding hydrochloric acid addition salt thereof, m.p. 209° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]([CH3:50])[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]([CH3:50])[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CN(CCCCl)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21)C(=O)OC(C)(C)C

Procedure:
N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (280 mg, 528 μmol), tert-butyl 3-chloropropyl(methyl)carbamate (110 mg, 528 μmol) and cesium carbonate (516 mg, 1.58 mmol) in dimethylformamide (4 mL) were heated in a microwave at 100° C. for 30 min. The mixture was partitioned between ethyl acetate and water, then the organic phase washed with water 3 times, dried, filtered and concentrated. The crude residue was used in the next step without purification. MS (M+H)+=702.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(#N)C>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CC#N
Product: Clc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
In a nitrogen stream, triethylsilane (2.8 mL, 17.6 mmol) and a boron trifluoride-diethyl ether complex (1.84 mL, 14.6 mmol) were added to a solution of (2-benzyloxyphenyl)-(4-chlorophenyl)methanol (4.76 g, 14.6 mmol) in acetonitrile (150 mL) at −40° C. and the reaction mixture was stirred at the same temperature for 2 hours and furthermore at 0° C. for one hour. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (3.85 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:23][CH2:24][C:25]1[C:26](=[O:35])[NH:27][C:28]([CH3:34])=[CH:29][C:30]=1[CH2:31][CH2:32][CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:23][CH2:24][C:25]1[C:26](=[O:35])[NH:27][C:28]([CH3:34])=[CH:29][C:30]=1[CH2:31][CH2:32][CH3:33])=[O:9]
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Cl)cc(N(CC)C2CCN(C)CC2)c1C
Temperature: 23 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a stirred solution of 5-chloro-3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methylbenzoic acid (crude material, 1.80 g, 3.26 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-1,2-dihydropyridin-2-one HCl salt (916 mg, 4.24 mmol) in DMSO (10 mL) was added PyBOP (3.10 g, 5.87 mmol) and hunig base (1.20 g, 9.78 mmol). The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 Ethylacetate/MeOH=10/1) to give the titled compound as a white solid (264 mg, 17% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.20 (t, J=5.9 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 5.96 (s, 1H), 4.54 (d, J=5.9 Hz, 2H), 3.02 (q, J=7.0 Hz, 2H), 2.81 (m, 2H), 2.64-2.71 (m, 3H), 2.21-2.27 (s×3, 9H), 1.84-1.94 (m, 2H), 1.55-1.65 (m, 6H), 1.00 (t, J=7.4 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M+H] 473.1, [M+Na] 495.3; HPLC 94.7% purity.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([I:11])[CH:10]=1)[NH2:6].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[I:11][C:9]1[CH:8]=[CH:7][C:5]([NH:6][S:21]([CH3:20])(=[O:23])=[O:22])=[C:4]([CH:10]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(I)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(I)ccc1NS(C)(=O)=O
Reaction time: 0.75 h
Yield: 46 %

Procedure:
To a solution of 5-iodoanthranilic acid methyl ester (1.00 g) and triethylamine (1.01 mL) in CH2Cl2 (25 mL) is added methanesulfonyl chloride (0.59 ml) at 0° C. The ice bath is removed and after 3 h at room temperature the solution is poured into water (20 mL) and extracted with CH2Cl2 (2×20 mL). The organic layers are combined, dried over MgSO4 and the solvent removed in vacuo. The resulting residue is dissolved in CH3OH (20 mL) and sodium methoxide (20 mL) is added. After 45 min, the solvent is removed in vacuo. The residue is diluted with Et2O (20 mL) and washed with water (20 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude black liquid is purified by silica gel column chromatography (4/1, hexanes/EtOAc) to afford 0.58 g (46%) of the title compound as a brown solid. Physical characteristics: m.p. 119-120° C.; 1H NMR (300 MHz, CDCl3) δ10.41, 8.36, 7.82, 7.52, 3.94, 3.06; IR (diffuse reflectance) 1700, 1682, 1483, 1385, 1335, 1328, 1307, 1249, 1213, 1159, 1147, 1093, 1086, 978, 971 cm−1; MS (FAB) m/z 356 (MH+); HRMS (FAB) m/z 355.9447 (C9H10INO4S+H). Anal. Found: C, 30.49; H, 2.88; N, 3.96.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[Br:15]Br>O>[Br:15][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)c(Br)c1
Reaction time: 5 h
Yield: 170.7 %

Procedure:
4-Nitrophenol (5 g, 35.9 mmol) was added to acetic acid (20 ml) and to the mixture, there was slowly added a solution of a mixture of bromine (0.93 ml, 18 mmol) and acetic acid (5 ml) at 85° C. The reaction mixture was stirred at the same temperature for 5 h and, thereafter, it was added to water and subjected to extraction with ethyl acetate. The organic extract was concentrated and the residue was subjected to column chromatography using a 7:3:1 solvent system of cyclohexane, ethyl acetate and methanol as an eluent to yield the end compound 2-bromo-4-nitrophenol (6.7 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:22](O)=[O:23])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[NH:17][C:16]=12.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:23])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[NH:17][C:16]=12
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc2c1C
Reactant: C1COCCN1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C(=O)N3CCOCC3)cc2c1C
Yield: 69 %

Procedure:
In accordance with the same procedures as in Step 1 of Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 and morpholine, the titled compound was obtained as a white solid. (Yield: 69%)
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C1C=CC=CC=1.CO>[I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cccc(C(=O)O)c1I
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cccc(C)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 2-iodo-3-methylbenzoic acid (500 mg, 0.48 mmol) in benzene/MeOH (2 mL, 10:1) was added TMSCHN2 (1 mL, 2N), the reaction mixture was stirred at rt for 30 min and then concentrated. The crude product was purified by flash chromatography (0 to 10% EtOAc/Hexanes, gradient) to afford 500 mg (91%) of Intermediate 299.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH:32]1[CH3:37]>C(Cl)Cl>[CH3:37][CH:32]1[N:31]([CH3:30])[CH2:36][CH2:35][N:34]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH:9]3[NH:10][C:11]4[C:12]5[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=5[CH:18]=[CH:19][CH:20]=4)[CH:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:29][CH:28]=2)[CH2:33]1
Reactant: CC1CNCCN1C
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Solvent: ClCCl
Product: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.52 mmol), 1,2-dimethylpiperazine (311 mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight, then NaBCNH3 (129 mg, 2.08 mmole) was added and the mixture was stirred for another 5 hours. After removal of solvents, the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (70 mg, 26%). LC-MS (ESI) m/z: 484 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43 (d, J=5.2 Hz, 3H), 2.84 (s, 3H), 3.29 (m, 1H), 3.33-3.44 (m, 6H), 4.03 (s, 2H), 4.22 (m, 1H), 4.65 (m, 1H), 6.91 (m, 1H), 6.97 (m, 1H), 7.00 (d, J=8 Hz, 2H), 7.23-7.37 (m, 4H), 7.65 (m, 1H), 7.77 (d, J=7.2 Hz, 1H), 9.92 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[CH2:15][OH:16])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[CH:15]=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)c(CO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)OC(C)(C)C)c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Compound 16A (6.33 mmol, 1.5 g) was dissolved in 75 mL of CH2Cl2 and then MnO2 (75 mmol, 6.55 g) was added. The black suspension was stirred overnight at r.t. and then filtered through a pad of celite. The celite pad was washed with CH2Cl2 and the combined filtrates were dried over Na2SO4. The solvent was filtered and the solvent was removed in vacuo to yield (2-formyl-4-methyl-phenyl)-carbamic acid tert-butyl ester as yellow thick oil (1.45 g). MS (electrospray): mass calculated for C13H17NO3, 235.12; m/z found 236, [M+H]+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:6][CH:5]=1.N1C2C(=CC=CC=2)C=CC=1>CCOCC>[Br:1][CH2:14][CH:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[O:15]1
Reactant: BrBr
Reactant: C=CCCC(O)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Product: Clc1ccc(C2CCC(CBr)O2)cc1
Yield: 18.1 %

Procedure:
16 g (0.1 mole) of bromine are added dropwise to 17.3 g (0.1 mole) of 5-(4-chlorophenyl)-pent-1-en-5-ol in 50 ml of absolute ether at 0° C. When the addition has ended, 13 g (0.1 mole) of quinoline are added, whereupon the temperature rises to 15° C. and quinoline hydrobromide precipitates. The precipitate is filtered off with suction, the filtrate is evaporated in vacuo and the residue is heated on a waterbath for 1 hour. After cooling, the residue is taken up in ether, the mixture is washed with 15% strength hydrochloric acid and with water, dried over sodium sulphate and concentrated in vacuo and the residue is distilled under a high vacuum. 5 g (18% of theory) of 2-bromomethyl-5-(4-chlorophenyl)tetrahydrofuran of boiling point 145° C./0.13 mbar are obtained. ##STR111##