Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][Cl:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.CCN(CC)CC.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1[C:48]2[C:39](=[N:40][C:41]3[C:46]([C:47]=2[NH:49][C:50]2[CH:51]=[C:52]([CH:54]=[C:55]([CH2:57][OH:58])[CH:56]=2)[NH2:53])=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl.CN(C=O)C>[CH:35]1[C:48]2[C:39](=[N:40][C:41]3[C:46]([C:47]=2[NH:49][C:50]2[CH:51]=[C:52]([NH:53][C:27]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([N:5]([CH2:13][CH2:14][Cl:15])[CH2:4][CH2:3][Cl:2])=[CH:7][CH:8]=4)=[O:33])[CH:54]=[C:55]([CH2:57][OH:58])[CH:56]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N(CCCl)CCCl)cc1)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reaction time: 0.5 h

Procedure:
To a solution of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (18, 0.306 g, 1.0 mmol) in dry CHCl3 (35 mL) containing Et3N (0.2 mL) was added dropwise a solution of triphosgene (115 mg, 0.4 mmol.) in an ice bath with vigorous stirring for 30 min. The reaction mixture was evaporated and the residue diluted with THF (20 mL), filtered through a pad of Celite, washed with THF (5 mL). The filtrate and washings were combined and was added dropwise into a solution of 3-(acridin-9-yl)amino-5-hydroxymethylaniline (6, AHMA)18 (0.351 g, 1.0 mmol) in dry DMF (10 mL) containing Et3N (0.5 mL) at 0° C. After being stirred for 18 h, the reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in a mixture of CHCl3/MeOH, mixed with silica gel (5 gm) and evaporated in vacuo to dryness. The residue was put on the top of a silica gel column (2×20 cm) and chromatographed using CHCl3/MeOH (100:5 v/v) as eluent. The fractions containing the main product were combined and evaporated in vacuo to dryness and residue was recrystallized from CHCl3/MeOH to give 1-[3-(acridin-9-ylamino)-5-hydroxymethylphenyl]-3-{4-[bis(2-chloroethyl)amino]phenyl}urea (BO-1037), 205 mg (35%); mp 173-175° C.; 1H NMR (DMSO-d6) δ 3.67 (8H, m, 4×CH2), 4.41 (2H, d, J=6.0 Hz, CH2), 5.14 (1H, t, J=6.0 Hz, exchangeable, OH), 6.37 (1H, s, ArH), 6.68 (2H, d, J=9.1 Hz, 2×ArH,), 6.81 (1H, s, ArH), 7.01 (1H, s, ArH), 7.05-7.19 (1H, m, ArH), 7.24 (2H, d, J=9.1 Hz, 2×ArH), 7.55 (4H, m, 4×ArH) 8.05 (2H, m, 2×ArH), 8.25 (1H, m, ArH) 8.46 (1H, m, ArH), 10.48 (1H, brs, exchangeable, NH). Anal. Calcd. for (C31H29Cl2N5O2): C, 63.81; H, 5.18; N, 12.00. Found: C, 64.07; H, 5.26; N, 11.87.
Reaction SMILES: C1(C)C=CC=CC=1.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10][CH:9]=1.[N:29]12CC[CH:32]([CH2:33][CH2:34]1)[CH:31](O)[CH2:30]2.[H-].[Na+]>C(O)C>[N:8]1[CH:9]=[CH:10][C:11]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH:27]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[O:25])=[CH:12][CH:13]=1
Reactant: CCOC(=O)N1CCc2ccccc2C1c1ccncc1
Reactant: OC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(OC1CN2CCC1CC2)N1CCc2ccccc2C1c1ccncc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a 50 ml toluene suspension containing 720 mg of ethyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate and 973 mg of 3-quinuclidinol, 102 mg of sodium hydride (60%) was added at room temperature. The resulting mixture was heated under reflux for 5 hours and 40 minutes while the resulting ethanol was removed together with toluene. The reaction mixture was cooled to room temperature, followed by addition of 20 ml of water. The resulting mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=100:2:1), thereby 827 mg of 3-quinuclidinyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate were obtained as yellow oil. The resulting oil was dissolved in 5 ml of ethyl acetate, 2 ml of a 4N hydrogen chloride in ethyl acetate solution was added. The solvent was then removed under reduced pressure. Ethanol and ether were added to the residue, and the crude crystals thus obtained was recrystallized from ethanol and ether, thereby 402 mg of 3-quinuclidinyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate dihydrochloride was obtained as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH2:12])=[S:11].Br[CH2:14][C:15]([C:17]1[CH:26]=[CH:25][C:24]2[NH:23][C:22](=[O:27])[C:21]3[NH:28][CH:29]=[CH:30][C:20]=3[C:19]=2[CH:18]=1)=O.[CH2:31]([C:33]([O-:35])=[O:34])[CH3:32]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[S:11][CH:14]=[C:15]([C:17]2[CH:26]=[CH:25][C:24]3[NH:23][C:22](=[O:27])[C:21]4[NH:28][CH:29]=[CH:30][C:20]=4[C:19]=3[CH:18]=2)[N:12]=1.[CH2:31]([C:33]([O-:35])=[O:34])[CH3:32]
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: NC(=S)Nc1c(Cl)cccc1Cl
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=c1[nH]c2ccc(-c3csc(Nc4c(Cl)cccc4Cl)n3)cc2c2cc[nH]c12
Temperature: 90 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
87 mg (1.2 mmol) of (2,6-dichlorophenyl)-thiourea is added to a suspension of 124 mg (0.33 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3.5 mL of ethanol. The mixture is stirred at 90° C. for 6 hours then the mixture is cooled to room temperature. The solvent is evaporated, then the product is purified by preparative LCMS. After drying, 43 mg (26%) of 8-[2-(2,6-dichlorophenylamino)-thiazol-4-yl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 79.1 %

Procedure:
To a suspension of tert-butyl chloroacetate (3.49 g, 34.9 mmol) and potassium carbonate (5.50 g, 39.8 mmol) in acetonitrile (300 mL) was added dropwise 1-methylpiperazine (5.00 g, 33.2 mmol), and the mixture was stirred with heating at 50° C. for 16 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated. Water (150 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (5.63 g, 79%) as a pale-yellow oil. The compound was used for the next reaction without further purification operation.
Reaction SMILES: [NH2:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:13]2[CH2:18][CH2:17][C@:16]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])[CH3:12])=[CH:7][CH:6]=1.C[Si]([N:37]=[C:38]=[O:39])(C)C>>[OH:29][C:26]([CH3:27])([CH3:28])[CH2:25][C@@:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:15][C:14](=[O:30])[N:13]([C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH:1][C:38]([NH2:37])=[O:39])([CH3:31])[CH3:32])=[CH:6][CH:7]=2)[CH3:12])[CH2:18][CH2:17]1
Reactant: C[C@@H](c1ccc(C#CC(C)(C)N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: C[Si](C)(C)N=C=O
Product: C[C@@H](c1ccc(C#CC(C)(C)NC(N)=O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 15 using (S)-3-((S)-1-(4-(3-amino-3-methylbut-1-ynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and trimethylsilyl isocyanate. LC-MS Method 1 tR=1.43 min, m/z=463; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.47 (d, 3H), 1.67 (s, 6H), 2.10-2.30 (4H), 2.38 (m, 1H), 2.77 (m, 1H), 5.58 (q, 1H), 6.78 (d, 1H), 7.08 (d, 1H), 7.30-7.40 (5H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[C:32]2[C:27](=[C:28]([Cl:33])[CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][OH:44])=[CH:37][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[C:32]2[C:27](=[C:28]([Cl:33])[CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:37][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cn(Cc3ccc(OCCO)cc3)c3c(Cl)cccc23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](c2cn(Cc3ccc(OCCOS(C)(=O)=O)cc3)c3c(Cl)cccc23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-7-chloro-1-[4-(2-hydroxyethoxy)benzyl]-1H-indole (0.23 g) and triethylamine (0.076 mL) in dichloromethane (4 mL) was added methanesulfonyl chloride (0.034 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-7-chloro-1-{4-[2-(methanesulfonyloxy)ethoxy]-benzyl}-1H-indole (0.25 g).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:10]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:9][N:8]([CH2:20][C:21](=[O:37])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]3=[O:35])=[CH:25][C:24]=2[F:36])[CH2:7]1)=[O:5])C.O[Li:39].O>C1COCC1.O>[Cl:19][C:16]1[S:15][C:14]([C:12]([NH:11][C@H:10]2[CH2:9][N:8]([CH2:20][C:21](=[O:37])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]4=[O:35])=[CH:25][C:24]=3[F:36])[CH2:7][C@@H:6]2[C:4]([O-:5])=[O:3])=[O:13])=[CH:18][CH:17]=1.[Li+:39]
Reactant: CCOC(=O)[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Reactant: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](C(=O)[O-])C1)Nc1ccc(-n2ccccc2=O)cc1F
Product: [Li+]
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
(3S,4R)-4-[(5-Chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-3-carboxylic acid ethyl ester (example 40.4; 0.11 g) is dissolved in THF/water (1:1; 3 ml) and LiOH hydrate (9 mg) is added to the suspension. The mixture is stirred for 2 h at 25° C. The solvent is evaporated to dryness to obtain 0.102 g (95%) lithium (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-3-carboxylate. White solid. MS 519.3 [M+H+].
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:10]([CH:12]([N:20]2[CH2:25][CH2:24][CH:23]3[S:26][C:27](=[O:29])[CH:28]=[C:22]3[CH2:21]2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:11])[CH2:9][CH2:8]1.[H-].[Na+].[C:32](OCC)(=[O:34])[CH3:33]>CN(C)C=O.C(OC(=O)C)(=O)C>[C:32]([O:29][C:27]1[S:26][C:23]2[CH2:24][CH2:25][N:20]([CH:12]([C:10]([CH:7]3[CH2:8][CH2:9]3)=[O:11])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH2:21][C:22]=2[CH:28]=1)(=[O:34])[CH3:33]
Reactant: O=C1C=C2CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Reaction time: 0.33 h
Yield: 65 %

Procedure:
2.6 g (7.8 mmole) of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine pyridine (prepared as described in Example 20) were dissolved in a mixture of 10 ml of dimethylformamide and 5 ml of acetic anhydride, and then 0.35 g (8.6 mmole) of a 60% w/w dispersion of sodium hydride in mineral oil was added to the resulting solution, whilst ice-cooling; the mixture was then stirred for 20 minutes at the same temperature, after which it was stirred for a further 3 hours at room temperature. At the end of this time, 300 ml of ethyl acetate were added to the mixture, which was then washed four times, each time with 50 ml of a saturated aqueous solution of sodium chloride The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, using a 100:3 by volume mixture of toluene and ethyl acetate as the eluent, to give a yellow oil. This oil was crystallized from diisopropyl ether, to obtain the title compound as white crystals, melting at 120°-121.5° C., in a yield of 65%.
Reaction SMILES: [H-].[Na+].C(S)C.[CH2:6]([C:8]1[O:19][C:11]2=[C:12]([O:17]C)[N:13]=[CH:14][C:15]([Br:16])=[C:10]2[CH:9]=1)[CH3:7].O>CN(C)C=O>[Br:16][C:15]1[C:10]2[CH:9]=[C:8]([CH2:6][CH3:7])[O:19][C:11]=2[C:12](=[O:17])[NH:13][CH:14]=1
Reactant: CCc1cc2c(Br)cnc(OC)c2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCS
Solvent: CN(C)C=O
Product: CCc1cc2c(Br)c[nH]c(=O)c2o1
Temperature: 150 °C
Yield: 89.4 %

Procedure:
To a stirred solution of sodium hydride (50 mg) (60% suspension in mineral oil) in dry N,N-dimethylformamide (3 ml) under an atmosphere of dry nitrogen at room temperature was added dropwise a solution of ethanethiol (0.09 ml) in N,N-dimethylformamide (3 ml). After stirring for 10 mins a solution of 2-ethyl-4-bromo-7-methoxyfuro[2,3-c]pyridine (200 mg) in N,N-dimethylformamide (5 ml) was added dropwise and the reaction mixture heated at 150° C. for 60 mins. Water (5 ml) was added and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed with ammonium chloride solution (25 ml), water (25 ml) and brine (25 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with ethyl actate afforded the title compound as a white solid (169 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:22](O)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[OH:61][CH:62]1[CH2:65][NH:64][CH2:63]1>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([C:22]([N:64]5[CH2:65][CH:62]([OH:61])[CH2:63]5)=[O:23])[CH:25]=[CH:26][C:27]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: OC1CNC1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)N2CC(O)C2)ccc1Cl
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a mixture of 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (2.5 g, 5.07 mmol) in THF (50 mL) was added EDCI (1.94 g, 10.14 mmol), HOBt (1.03 g, 7.61 mmol), DIPEA (5 mL) and 3-hydroxyazetidine hydrochloride (0.83 g, 7.61 mmol) by sequence under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water, extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (eluted by hexanes:EtOAc=1:2) to give 8-bromo-N-(2-chloro-5-(3-hydroxyazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (1.6 g, yield 58%). LC-MS: (ESI, m/z)=547 [M+H]+
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:12]1([C:11]2[C:6]([CH:4]3[CH2:5][N:2]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:3]3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: c1cnc(N2CCCCC2)c(C2CNC2)n1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2nc(N3CC(c4nccnc4N4CCCCC4)C3)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 2-azetidin-3-yl-3-piperidin-1-yl-pyrazine hydrochloride (127 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs2CO3 (325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to give 2-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-quinoline (58 mg, 0.17 mmol yield 17%).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][NH:11][C@@H:12]([CH3:20])[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][N:11]([C@@H:12]([CH3:20])[CH:13]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[C:40](=[O:41])[C@@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]3[C:33]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2nsnc12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nsnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 67.6 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, (S)—N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1,1-diethoxypropan-2-amine (Compound IX-8) (1.41 g, 4.78 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (2.4 g, 5.23 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=7:3) to obtain the title compound (2.38 g, 68%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[C:5]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:4]=2[O:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[C:5]2[CH:15]=[C:16]([NH:19][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: CC1(C)N=C(n2ccccc2=O)c2cc(N)ccc2O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)C(n1ccccc1=O)=NC(C)(C)O2
Reaction time: 16 h

Procedure:
A mixture of 1 g of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-amino-2H-1,3-benzoxazine, 10 ml of acetic anhydride and 10 ml of pyridine is left to stand at 20° for 16 hours. The mixture is evaporated, and the residue is purified by chromatography to give 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-acetamido-2H-1,3-benzoxazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[C:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])[C:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:15][C:11]=2[C:12]([NH:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: Nc1cccnc1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Reaction time: 18 h

Procedure:
To a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)benzoic acid (may be prepared as described in Description 29; 12 mg, 0.02 mmol) in N,N-dimethylformamide (4 ml), was added diisopropylethylamine (4.15 μL, 0.02 mmol), 3-aminopyridine (2.23 mg, 0.02 mmol) and HATU (9.03 mg, 0.02 mmol). The reaction stirred for 18 hours, then the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a gum. 4.8 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]C(C)(C)C.[CH3:32][C:33]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:35]([OH:36])[C:34]1[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:33]=1[CH3:32])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Reactant: Cc1ccc(C=O)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2ccc(C)cc2C)sc2ncccc12
Yield: 73.3 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxy-methyl)thieno [2,3-b]pyridine-3-sulfonamide (0.18 g, 0.42 mmoles)[Example 4(A)], t-BuLi (1.7 M, 0.32 ml, 0.55 mmoles), THF (5 ml) and 2,4-dimethylbenzaldehyde (0.12 ml, 0.84 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 0.17 g (73%) of the title compound.
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.O>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:14][N:13]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[CH:23]=2)=[CH:18][CH:17]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution (70 ml) of methyl 4-[chloro(hydroxyimino)methyl]benzoate (1.65 g) and 4-chloro-ethynylbenzene (1.06 g) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (2.5 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-tetrahydrofuran to give methyl 4-[5-(4-chlorophenyl)-3-isoxazolyl]benzoate (2.20 g, yield 91%) as colorless crystals. melting point: 225–226° C.