Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[C:5]2=[N:6][CH:7]=1.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(O)CCO>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:23]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:12]=4)[C:5]3=[N:6][CH:7]=2)=[CH:24]1
Reactant: OB(O)c1ccoc1
Reactant: Brc1cnc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCCO
Solvent: COCCOC
Product: c1cncc(-c2cccc(-n3cnc4cc(-c5ccoc5)cnc43)c2)c1
Temperature: 90 °C
Yield: 61.5 %

Procedure:
A suspension of 6-bromo-3-[3-(pyridin-3-yl)phenyl]-3H-imidazo[4,5-b]pyridine (351 mg, 1 mmol), 3-furanboronic acid (168 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg) and 1,3-propanediol (360 μl, 5 mmol) in 1,2-dimethoxyethane (6 ml) and 2M sodium carbonate solution (3 ml) was heated at 90° C. for 16 hours. The reaction was cooled and partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was then washed with brine, dried over anhydrous sodium sulphate, filtered and pre-adsorbed on to silica. Purification by silica gel chromatography eluting with dichloromethane/methanol/0.88 NH3 (95:4.5:0.5) furnished the title compound as a cream-coloured solid (208 mg, 62%), m.p. 191-192° C. (Found C, 73.13; H, 3.93; N, 16.01. C21H14N4O. 0.4H2O requires C, 72.99; H, 4.32; N, 16.21); δH (400 MHz, d6-DMSO) 7.17 (1H, s), 7.54-7.57 (1H, m), 7.74-7.85 (3H, m), 8.09 (1H, d, J 8), 8.22 (1H, d, J 8), 8.35 (2H, d, J 6), 8.50 (1H, s), 8.63 (1H, d, J 4), 8.80 (1H, s), 9.05 (1H, s), 9.07 (1H, s); m/z (ES+) 339 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20]Br>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: Cc1ccc(C(=O)O)cc1
Product: COc1ccc(Br)c(CCc2ccc(C(=O)O)cc2)c1

Procedure:
The title compound was prepared from 4-methylbenzoic acid and 1-bromo-2-(bromomethyl)-4-methoxybenzene using the procedure described for the preparation of INTERMEDIATE 10. 1H NMR (400 MHz, CD3OD): δ 7.90 (d, J=8.3 Hz, 2H); 7.40 (d, J=8.7 Hz, 1H); 7.27 (d, J=8.2 Hz, 2H); 6.72-6.66 (m, 2H); 3.68 (s, 3H); 3.01-2.91 (m, 4H). LCMS1 3.68 min. (M-OH)=317
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.N1CCCCC1>[CH:12](=[C:2]1[C:1](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CC(=O)c2ccccc21
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccccc2)C(=O)c2ccccc21
Reaction time: 24 h
Yield: 72.1 %

Procedure:
To a solution of 1,3-indandione (43.8 g) and piperidine (44 mg) in dry benzene (500 ml) was added benzaldhyde (31.8 g). The mixture was heated to reflux and the water generated was removed by Dean-Stark trap. After 24 hours, the mixture was evaporated to dryness. The residue was recrystallized from ethanol (200 ml) to give 2-benzylidene-1,3-indandione as a yellow solid (50.6 g).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19][S:20][CH2:21][CH2:22]/[N:23]=[C:24](/[NH:27][C:28]#[N:29])\[NH:25][CH3:26].C(O)(=O)CCCCCCCCCCCCCCCCC>ClCCl>[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19][S:20][CH2:21][CH2:22]/[N:23]=[C:24](/[NH:27][C:28]#[N:29])\[NH:25][CH3:26].[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CN/C(=N\CCSCc1nc[nH]c1C)NC#N
Solvent: ClCCl
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O

Procedure:
0.88 g (0.5 cmole) of ascorbic acid and 1.26 g (0.5 cmole) of cimetidine were added to a solution of stearic acid (2.14 g) in dichloromethane (q.s.). The mixture was filtered without washing and dried. Weight: 2.5 g. A stereoscopically homogenous white solid. Is unaltered by ambient conditions.
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)(Cl)=O.[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:40][O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[C:37](O)=[O:38])[N:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.Cl.[NH2:50][CH:51]1[C:68](=[O:69])[N:53]2[C:54]([C:65]([O-:67])=[O:66])=[C:55]([CH2:58][N+:59]3([CH3:64])[CH2:63][CH2:62][CH2:61][CH2:60]3)[CH2:56][S:57][C@H:52]12>O1CCCC1.O>[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:40][O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[C:37]([NH:50][CH:51]2[C:68](=[O:69])[N:53]3[C:54]([C:65]([O-:67])=[O:66])=[C:55]([CH2:58][N+:59]4([CH3:64])[CH2:63][CH2:62][CH2:61][CH2:60]4)[CH2:56][S:57][C@H:52]23)=[O:38])[N:35]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)CCCC1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NOC4CCCCO4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)CCCC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 175.1 %

Procedure:
To a mixture of dimethylformamide (5.28 ml) and tetrahydrofuran (15 ml) wasadded phosphorus oxychloride (6.6 ml) under cooling. The mixture was stirred for 30 minutes under ice-cooling. To the mixture was added a solution of 2-(2-tritylaminothiazol-4-yl)-2-(2-tetrahydropyranyloxyimino)acetic acid (syn isomer) (30.4 g) in tetrahydrofuran (300 ml) with stirring under ice-cooling. The mixture was stirred for 40 minutes at 3° to 5° C. to produce an activated acid solution. On the other hand, to a solution of a salt of 7-amino-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate dihydrochloride (20 g) in tetrahydrofuran containing monotrimethylsilylacetamide (107 g) was added at once. The activated acid solution obtained above under cooling at -20° C. and the resulting mixture was stirred for 2 hours at -20° C. to -10° C. To thereaction mixture was added water. The insoluble materials were filtered offand the organic layer in the filtrate was separated. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate several times. The combined extract was washed with water, aqueous sodium bicarbonate and saturated aqueous sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (250 g) eluting with a mixture of ethyl acetate and isopropyl ether (1:3). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated in diisopropyl ether to give 7-[2-(2-tritylaminothiazol-4-yl)-2-(2-tetrahydropyranyloxyimino)acetamido]-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate (syn isomer) (75.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:3]=1.[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1N2CCN(CC2)C1.O.CC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:5]=[C:6]([NH:36][S:33]([C:30]2[CH:29]=[CH:28][C:27]([CH3:26])=[CH:32][N:31]=2)(=[O:35])=[O:34])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: Cc1ccc(S(N)(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1Cl
Agent: C1CN2CCN1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1NS(=O)(=O)c1ccc(C)cn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 93.8 %

Procedure:
12.5 g (33.5 mmol) of 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidine-2-yl]-pyridine-2-carbonitrile and 6.06 g (35 mmol) of 5-methyl-pyridine-2-sulfonamide were added to 130 ml of acetone. 15 g of potassium carbonate and 190 mg (1.6 mmol) of 1,4-diazobicyclo[2.2.2]octane were added and the suspension was stirred at 40° C. for 5 hr and at 20° C. for 15 hr. Then 50 ml of de-ionized water were added followed by dropwise addition of 50 ml of 3 N hydrochloric acid (pH of the solution=1). Acetone was removed by evaporation and the suspension was stirred for 1 hr. The solid was filtered and washed with 100 ml of water. The residue was heated (reflux) in 100 ml of methanol for 1 hr followed by cooling to 20° C. The solid was filtered and dried at 80° C., 2000 Pa for 16 hr. There were obtained 16.0 g (93% of theory) of 5-methyl-pyridine-2-sulfonic acid [6-chloro-2-(2-cyano-pyridine-4-yl)-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide with a HPLC purity of 90.3% (w/w).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][CH2:11][N:12]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:37])[C@@H:19]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[C:28]([Cl:36])[CH:27]=2)[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:13]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[NH2:7][CH2:8][C:9]#[C:10][CH2:11][N:12]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:37])[C@@H:19]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[C:28]([Cl:36])[CH:27]=2)[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:13]1
Reactant: CC(C)(C)OC(=O)NCC#CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC#CCN)n2)cc1Cl
Yield: 64.3 %

Procedure:
(4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-but-2-ynyl)-carbamic acid tert-butyl ester (240 mg, 0.43 mmol) was dissolved in methylene chloride (10 mL) and trifluoroacetic acid (2 mL) was added while stirring. The reaction continued to stir for 45 min. The reaction was concentrated in vacuo at 0° C. to give a yellow oil. The reaction was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate (2×50 mL), saturated aqueous brine solution (50 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% methanol/ethyl acetate to 10% methanol/ethyl acetate) afforded N-[1-(4-amino-but-2-ynyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (128 mg, 69%) as a thick, faintly yellow oil: ESI-LRMS m/e calcd for C22H27ClN4O3S [M+] 462.2, found 463.2 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.21 (m, 2H, CH2), 1.38-1.82 (m, 8H, 4×CH2), 1.98 (brs, 2H, NH2), 2.05-2.24 (m, 1H, CH), 3.29 (t, J=2.0 Hz, 2H, NCH2), 3.33 (s, 3H, SO2CH3), 3.86-3.95 (m, 1H, CH), 4.87 (t, J=2.0 Hz, 2H, NCH2), 6.44 (d, Jo=2.3 Hz, 1H, Ar), 7.58 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.62 (d, Jo=2.3 Hz, 1H, Ar), 7.68 (d, Jm=1.6 Hz, 1H, Ar), 7.99 (d, Jo=8.2 Hz, 1H, Ar), 10.81 (s, 1H, NH).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-:8])=[O:7]>>[OH:15][C:10]1[CH:11]=[CH:12][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=S(=O)(O)Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 63.5 %

Procedure:
To a solution of chlorosulfonic acid (12.0 mL, 180 mmol) at 0° C. was added 2-nitrophenol (8.35 g, 60.0 mmol) in small portions over 1 h. The reaction was heated to 60° C. for 20 minutes and allowed to stir for 18 h at 25° C. The reaction was quenched by pouring it into 100 g of ice. The reaction was extracted with chloroform (3×), washed with cold water (2×), dried over MgSO4, filtered, and concentrated to give 9.06 g (64%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]#[CH:12])=O)=[CH:4][CH:3]=1.[BrH:13]>C(OCCC)(=O)C>[Br:13][CH2:12][C:11]1[C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:8][CH:10]=1
Reactant: Br
Reactant: C#CCS(=O)c1ccc(C)cc1
Solvent: CCCOC(C)=O
Product: Cc1ccc2scc(CBr)c2c1
Temperature: 100 °C
Yield: 88 %

Procedure:
In 445 mL of propyl acetate, was dissolved the compound obtained in Example 11 (29.7 g, 167 mmol). The resulting solution was heated at 100° C. for 1 hour. The solution was then cooled with ice to keep the internal temperature of the reaction system at 10° C. To the cooled solution, was added 22.8 mL of a 48% hydrobromic acid. The obtained mixture was allowed to stand under cooling with ice for 1 hour and 30 minutes. The aqueous layer was separated, and the organic layer was washed with 50 mL of water, dried with magnesium sulfate, vacuum concentrated and dried to obtain 35.3 g of a brown transparent oil 3-(bromomethyl)-5-methylbenzo[b]thiophene. (yield=88%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[C:25]5=[N:26][NH:27][C:28](=[O:33])[C:29]6[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=65)[NH:22][CH:21]4[C:34]4[CH:39]=[CH:38][C:37]([CH:40](OCC)[O:41]CC)=[CH:36][CH:35]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]4[C:25]5=[N:26][NH:27][C:28](=[O:33])[C:29]6[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=65)[NH:22][CH:21]4[C:34]4[CH:39]=[CH:38][C:37]([CH:40]=[O:41])=[CH:36][CH:35]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:10][CH2:11]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (280 mg, 0.45 mmol) in 3N hydrochloric acid (10 mL) was stirred at room temperature for 3 hr. Then the mixture was neutralized with potassium carbonate. The resulting suspension was filtered to give 4-(9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (220 mg, yield 89%) as a light yellow solid. LC-MS (ESI) m/z: 548 (M+1)+.
Reaction SMILES: Cl.[O:2]1[C:12]2[CH:11]=[C:10]([CH2:13][NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]4[C:32]5[C:27](=[N:28][CH:29]=[C:30](F)[CH:31]=5)[CH:26]=[CH:25][C:24]4=[O:34])[CH2:17][CH2:16]3)[N:9]=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1.[C:35](=O)([O-])[OH:36].[Na+]>C(Cl)(Cl)Cl>[O:2]1[C:12]2[CH:11]=[C:10]([CH2:13][NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]4[C:32]5[C:27](=[N:28][CH:29]=[C:30]([O:36][CH3:35])[CH:31]=5)[CH:26]=[CH:25][C:24]4=[O:34])[CH2:17][CH2:16]3)[N:9]=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCCO3)CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 85 mg of 1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant oily substance, 2 mL of methanol and 83 mg of a 28% sodium methoxide/methanol solution were added at room temperature, and the mixture was heated under reflux while stirring for 4 hours. After cooling to room temperature, water and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant residue was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 53 mg of 1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a light brown oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[N:6]=[C:5]([C:10]([OH:12])=O)[CH:4]=1.C1N=C[N:15](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-].O>CN(C=O)C.C(Cl)Cl>[Cl:9][C:7]1[N:6]=[C:5]([C:10]([NH2:15])=[O:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(Cl)nc(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(Cl)nc(C(N)=O)c1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a solution of 4-methoxy-6-chloro picolinic acid (25 mmol) in anhydrous DMF (48 mL) was added CDI (27.5 mmol) at 0° C. The reaction mixture was stirred for 5 min in an ice-bath and then stirred at room temperature. After the reaction was completed, NH4OH (190 mL) was added and the reaction mixture was stirred at room temperature for 6 hrs. The mixture was partioned between H2O (200 mL) and DCM (300 mL). The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel chromatography (eluent: DCM/CH3OH) to give compound 18 as a beige solid in 61% yield. MS (ESI, EI+): m/z=187.14 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[S:14]([C:17]1[C:25]2[C:21](=[N:22][S:23][N:24]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].N1C=CC=CC=1.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[NH:1][S:14]([C:17]1[C:25]2=[N:24][S:23][N:22]=[C:21]2[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of methyl 2-amino-4-chlorobenzoate (7.0 g, 37.7 mmol) in DCM (75 mL) at room temperature (rt) was added 4-chlorosulfonyl-2,1,3-benzothiadiazole (9.45 g, 39.6 mmol), pyridine (9.1 mL, 112 mmol), and DMAP (0.23 g, 1.88 mmol). The mixture was stirred at rt overnight, poured into 1 N HCl (200 mL), and extracted with DCM (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (hexanes/EtOAc) to afford the title sulfonamide as a tan solid (11.65 g, 80%). MS (ESI−): mass calcd. for C14H10ClN3O4S2, 383.8; m/z found, 382 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.38 (s, 1H), 8.40 (dd, J=7.2, 1.2, 1H), 8.24 (dd, J=8.8, 1.2, 1H), 7.80 (d, J=8.4, 1H), 7.76 (d, J=2.0, 1H), 7.74 (dd, J=8.8, 7.2, 1H), 6.94 (dd, J=8.4, 2.0, 1H), 3.92 (s, 3H). Anal. calcd. for C14H10ClN3O4S2: C, 43.81; H, 2.63; N, 10.95. Found: C, 44.19; H, 3.00; N, 11.23.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][CH:13]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:14]([OH:16])=[O:15].[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:22][O:20][C:19]([CH2:18][CH2:17][CH:13]([CH2:12][S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:14]([OH:16])=[O:15])=[O:21]
Reactant: O=C(O)CCC(CSc1ccc2ccccc2c1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCC(CSc1ccc2ccccc2c1)C(=O)O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 1646.6 %

Procedure:
A mixture of 2-(2-naphthylthiomethyl)glutaric acid (28.8 g), methanol (300 ml), and p-toluenesulfonic acid (0.9 g) was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated in vacuo, and water was added to the resulting residue. The mixture was extracted with ethyl acetate, washed with water, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized from isopropyl ether to give 27.4 g of 2-(2-methoxycarbonylethyl)-3-(2-naphthylthio)propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:31]([O:33]C)=O)[C:11]3[NH:12][C:13]4[CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:16]=[CH:17][C:18]=4[C:19]=3[N:20]=2)=[CH:4][CH:3]=1.[NH3:35]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:31]([NH2:35])=[O:33])[C:11]3[NH:12][C:13]4[CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:16]=[CH:17][C:18]=4[C:19]=3[N:20]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1[nH]c1cc(OCCCN3CCOCC3)ccc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1[nH]c1cc(OCCCN3CCOCC3)ccc12
Temperature: 80 °C
Yield: 45 %

Procedure:
A suspension of crude methyl 2-(4-chlorophenyl)-7-(3-morpholinopropoxy)-5H-pyrido[3,2-b]indole-4-carboxylate (75 mg, 0.16 mmol) in 7 N NH3 in MeOH (4 mL) in a sealed microwave vial was heated at 80° C. overnight. The product was isolated by preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=30:70 to A:B=0:100 [A=10 mM NH4OAc in 5% aq. CH3CN; B=10 mM NH4OAc in 95% aq. CH3CN] over 20 min) followed by removal of the solvents on the SPEEDVAC® to leave 2-(4-chlorophenyl)-7-(3-morpholinopropoxy)-5H-pyrido[3,2-b]indole-4-carboxamide (34.6 mg, 0.071 mmol, 45% yield) as a yellow solid. MS (ESI) m/z 465.0 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (1H, s), 8.57 (1H, s), 8.37 (1H, s), 8.28-8.33 (2H, m), 8.11 (1H, d, J=8.56 Hz), 7.87 (1H, s), 7.54-7.63 (2H, m), 7.28 (1H, d, J=2.27 Hz), 6.88 (1H, dd, J=8.69, 2.14 Hz), 4.11 (2H, t, J=6.29 Hz), 3.59 (4H, br. s.), 2.45 (2H, br. s.), 2.32-2.45 (4H, m), 1.96 (2H, br. s.).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[N:18]2[C:13]([C:14]([NH2:19])=[N:15][CH:16]=[N:17]2)=[C:12]([C:20]2[CH:21]=[CH:22][C:23]3[C:27]([CH:28]=2)=[N:26][N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=3)[CH:11]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[NH2:19][C:14]1[C:13]2=[C:12]([C:20]3[CH:21]=[CH:22][C:23]4[C:27]([CH:28]=3)=[N:26][N:25]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:24]=4)[CH:11]=[C:10]([CH2:9][CH:7]3[CH2:8][CH:6]3[CH2:4][OH:3])[N:18]2[N:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)C1CC1Cc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Nc1ncnn2c(CC3CC3CO)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 2-[4-amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl]-cyclopropanecarboxylic acid ethyl ester (3.55 g, 7.6 mmol) in THF (106 mL) at 0° C. was added DIBAL (4.3 g, 30 mmol). The reaction mixture was stirred at rt for 1.5 hour. TLC analysis showed starting material, and 20 mL of DIBAL was added. The reaction mixture was stirred at rt for another 3 hours until no starting material was detected by TLC analysis. The reaction was quenched by saturated, aqueous NH4Cl. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by Biotage® (gradient 50%—100% EtOAc/hexane to 5% MeOH/EtOAc) to give the title product as an off-white solid, 2.5 g (yield 77%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.6 (m, 2 H), 3.4 (m, 2 H), 2.90 (m, 2 H), 1.2-1.0 (m, 2 H); ES-MS m/z 425.33 [M+H]+, HPLC RT (min) 2.93.