Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28](Cl)[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:33][CH3:34])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](=[O:38])([O-])[O-].[Cs+].[Cs+]>N1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([N:8]5[CH2:6][CH2:35][O:38][CH2:10][CH2:9]5)[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:33][CH3:34])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCN1
Product: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Yield: 90.6 %

Procedure:
0.30 g (0.60 mMol) 4-{2-[(2-chloro-pyridine-4-carbonyl)-amino]-4-methoxy-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester were heated to 130° C. for 24 h in 1 ml morpholine and 0.39 g (1.2 mMol) cesium carbonate. The morpholin has been removed in vacuo. The residue has been triturated in ethyl acetate and subsequently subjected to column chromatography (ethyl acetate) to yield 0.15 g (45%) 4-{4-methoxy-2-[(2-morpholin-4-yl-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow foam. ES-MS m/e (%): 552 ([M+H]−, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9]Cl.[C:17]1([CH3:29])[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9][N:26]1[CH2:27][CH2:28][N:23]([C:19]2[CH:18]=[C:17]([CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: Cc1nc2ccc(Cl)cn2c(=O)c1CCCl
Reactant: Cc1cccc(N2CCNCC2)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCN(CCc3c(C)nc4ccc(Cl)cn4c3=O)CC2)c1
Yield: 39.9 %

Procedure:
A mixture of 1.3 g of 2-methyl-3-(2-chloroethyl)-7-chloro-4H-pyrido[1,2-a]pyrimidin-4-one, 2.1 g of 1-(m-tolyl)piperazine and 20 ml of toluene was refluxed for 30 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by means of column chromatography using alumina and recrystallized from a mixture of ethanol and n-hexane to give 0.8 g of the desired compound as pale yellow scales, m.p. 119° - 120°C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[Li].[S:12]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20]Br)([OH:15])(=[O:14])=[O:13].O>C(O)C>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([S:7]([CH2:20][C:19]([NH:18][CH2:17][CH2:16][S:12]([OH:15])(=[O:14])=[O:13])=[O:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(CBr)NCCS(=O)(=O)O
Reactant: Cc1ccc(S(=O)O)cc1
Agent: [Li]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)CC(=O)NCCS(=O)(=O)O)cc1
Reaction time: 4 h
Yield: 89 %

Procedure:
To a 5-liter flask equipped with a mechanical stirrer and reflux condenser was added p-toluenesulfinic acid, lithium salt (308.57 g), N-(2-sulfoethyl)-2-bromoacetamide, lithium salt (527.39 g), water (180 ml), and ethyl alcohol (3380 ml). The resulting suspension was heated to reflux. After about an hour of reflux, nearly all of the reactants had dissolved. Reflux was continued another four hours, and the solution was filtered hot through a Celite pad to remove some haziness. The solution was cooled overnight to room temperature. The solid that formed was collected and washed with 1 liter of 95% ethyl alcohol/water. The white solid was air dried and then dried at high vacuum, providing 553.88 g (89% yield) of 2-(4-methylphenyl)sulfonyl-N-(2-sulfoethyl)acetamide, lithium salt (Intermediate 1). HPLC analysis showed no detectable impurities. Ion chromatography indicated 0.035 weight % bromide and 1.8 weight % lithium. The material exhibited an acceptable proton spectrum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>O1CCCC1.O>[C:17]([C:7]1[CH:6]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:4]=[CH:3][C:2]=1[F:1])([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)ccc1F
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 4-fluorobenzotrifluoride (75 ml) in tetrahydrofuran (570 ml) under a nitrogen atmosphere and at a temperature of approximately -60° C. was added butyl lithium (25N, 200 ml) over a period of one hour. The reaction mixture was stirred at from -70° to -60° C. for four hours and then was poured over an excess of dry ice. After fifteen minutes the excess dry ice was evaporated and the solvent removed to leave a residue. The residue was taken up in water (500 ml) and sodium hydroxide (1N, 30 ml) prior to washing with ethyl acetate (2×300 ml). The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2x300 ml). Finally, the combined organic extracts were washed with water (500 ml), dried and then evaporated to yield a crude residue which, upon recrystallisation from toluene/hexane, gave the title compound as a solid (77 g, 0.37 mol, 81% yield).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[N+]([O-])([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Br
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: [Cu]Br
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(=O)O)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of compound of Example 1a (73 g, 0.483 mol) in water (411 mL) and 47% HBr (486 mL) was stirred at 25° C. for 1 h and then the reaction mixture was cooled to −2° C. A solution of sodium nitrate (32 g, 0.463 mol) in water (100 mL) was added to the reaction mixture over a period of 15 min, maintaining the temperature at −1° C. to −2° C. The reaction mixture was stirred at −1° C. to −2° C. for 1.5 h. The reaction mixture was added slowly to a suspension of copper(I)bromide (73 g, 0.508 mol) in water (73 mL) and aqueous HBr (73 mL). The reaction mixture was stirred at 25° C. for 1 h and then digested at 70° C. for 1 h. The solid was filtered, washed with water till the pH of the filtrate was 7 and dried to obtain the title compound. Yield: 94 g (90%); 1H NMR (DMSO-d6, 300 MHz): δ 2.37 (s, 3H, CH3), 7.64 (m, 2H, Ar), 7.87 (s, 1H, Ar); MS: m/e (ES−) 214 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[CH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:7][C:6]=2[CH:32]=1.CCCCCC.C([Li])CCC.[C:44](=[O:46])=[O:45]>C1COCC1>[C:44]([C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[CH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:7][C:6]=2[CH:32]=1)([OH:46])=[O:45]
Reactant: Clc1ccc(C2CCN(CCC=C3Cc4cc(Br)ccc4Oc4ncccc43)CC2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc2c(c1)CC(=CCCN1CCC(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[3-(8-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidine (Example 160) (130 mg) in THF (1.0 ml) was added 1.6M n-butyllithium hexane solution (0.17 ml) at −78° C. After stirring 10 minutes at the same temperature, CO2 (dry-ice) was added to the mixture. After being warmed to ambient temperature, the mixture was stirred for 30 minutes at the same temperature. The mixture was concentrated in vacuo. The resulting oil was purified by silica gel chromatography eluted with dichloromethane -methanol (5:1) to give the titled compound.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:15][CH2:16][C:17](=O)[CH2:18][CH3:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([C:17]1[CH2:16][CH2:15][C@@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)[CH3:19]
Reactant: CCOC(=O)[C@H](CCC(=O)CC)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CCC(CC)=N1

Procedure:
Ethyl (2S)-2-((tert-butoxycarbonyl)amino)-5-oxoheptanoate and trifluoroacetic acid (3 mL) were stirred in dichloromethane (3 mL) at room temperature for 3 hours. The mixture was concentrated under reduced pressure to provide the titled compound. MS (ESI) m/z 170 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]2[CH2:11][CH:6]1[C:7](=[O:12])[O:8]2)=[O:4].[NH2:13][C@H:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:16][CH3:17].CCN(C(C)C)C(C)C.OC1C=CC=CN=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][C@@H:9]([OH:8])[CH2:11][C@H:6]1[C:7](=[O:12])[NH:13][C@H:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: COC(=O)C1CC2CC1C(=O)O2
Reactant: CCC[C@H](N)C(=O)OC(C)(C)C
Agent: Oc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC)C(=O)OC(C)(C)C
Yield: 95.8 %

Procedure:
Compound 41 (263 mg, 1.55 mmol) and H-Nva-OtBu (420 mg, 2.42 mmol) were dissolved in dry THF (20 mL). DIEA (530 uL, 3.04 mmol) and 2-hydroxypyridine (260 mg, 2.73 mmol) were added and the mixture was refluxed for five days. The solvent was evaporated and the crude product was purified by flash column chromatography (toluene/EtOAc 1:2) to give 42 (510 mg, 96%).
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:39](Cl)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:29]1([C:39]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](OC(=O)c3cccc4ccccc34)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Into a 25-mL RB-flask was added N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 1-naphthalenecarbonyl chloride (100 mg), diisopropylethylamine (0.30 mL) in THF (0.50 mL) at room temperature. After stirring for 16 hrs at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.70 mg, 71.3% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.90 (d, 1H, J=8.9 Hz), 8.28 (apparent dd, 1H, J=1.5, 7.2 Hz), 8.03 (d, 1H, J=8.7 Hz), 7.88 (dm, 2H, J=8.7 Hz), 7.60-7.48 (m, 7H), 7.40-7.32 (m, 3H), 7.25 (m, 1H), 6.90 (apparent d, 1H, J=7.4 Hz), 6.18 (apparent dd, 1H, J=5.7, 7.8 Hz), 3.42 (m, 2H), 2.84 (m, 2H), 2.53 (m, 2H), 2.44 (apparent sept, partially hidden, 4H, J=7.5 Hz), 2.30-2.10 (m, 2H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 535.6 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].Br.Br.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: N#CCCCCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 80 %

Procedure:
A mixture of 11 parts of 4-chlorobutanenitrile, 48.5 parts of 1-(4-fluorophenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 30 parts of sodium carbonate and 270 parts of DMF was stirred and heated overnight at 70° C. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized twice from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 2.2 parts (80%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinebutanenitrile; mp. 130.5° C. (90).
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([N:13]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=2[C:42]2[CH:47]=[C:46]([CH:48]([CH3:50])[CH3:49])[CH:45]=[CH:44][C:43]=2[O:51][CH3:52])[C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:16][N:15]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>O1CCOCC1.[Cl-].[Na+].O>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([N:13]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:33]=2[C:42]2[CH:47]=[C:46]([CH:48]([CH3:50])[CH3:49])[CH:45]=[CH:44][C:43]=2[O:51][CH3:52])[C:14]2[N:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][N:19]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-phenyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (197 mg) is added a 4N-hydrochloric acid in dioxane (2.5 ml) and the mixture is stirred at room temperature for 3 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 4-{2-[(3,5-bis-trifluoromethyl-phenyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (104 mg). MS (m/z): 716 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[CH:18][C:8]=2[NH:7][C:6]1=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]3.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH:5]3[O:10][C:9]4[CH:11]=[C:12]5[C:17](=[CH:18][C:8]=4[NH:7][C:6]3=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]5)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc3c(cc2OC1CCCBr)CCCC3
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cc3c(cc2OC1CCCN1CCN(c2ccc(F)cc2)CC1)CCCC3
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
A mixture of 2-(3-bromopropyl)-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one (3.1 g), 1-(4-fluorophenyl)piperazine (2.3 g), triethylamine (1.5 ml) and N,N-dimethylformamide (DMF)(100 ml) was stirred at 80° C. for 1.5 hour, which was diluted with ice-water and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), from which the solvent was distilled off. The residue was recrystallized from chloroform-ethyl acetate to give 2.4 g (59.3%) of 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one as colorless crystals, m.p. 164°-165° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1)[N:8]([CH3:27])[C:7]2=[O:28].IC1C=CC=C2C=1N=C([NH:40][C@H:41]1[CH2:46][CH2:45][CH2:44][C@@H:43]([NH:47][C:48](=[O:54])OC(C)(C)C)[CH2:42]1)N(C)C2=O.C[C@@H]1C2NC(B3OC(C)(C)C(C)(C)O3)=CC=2C(=O)N1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:27][N:8]1[C:7](=[O:28])[C:6]2[C:11](=[C:2]([C:41]3[NH:40][C:44]4[C@@H:43]([CH3:42])[NH:47][C:48](=[O:54])[C:45]=4[CH:46]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]1[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1
Reactant: Cn1c(N[C@H]2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(Br)cccc2c1=O
Reactant: Cn1c(N[C@H]2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(I)cccc2c1=O
Agent: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(N[C@@H]5CCC[C@H](NC(=O)OC(C)(C)C)C5)nc34)[nH]c21
Temperature: 80 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
A mixture of (rac)-tert-butyl ((1R,3S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate and (rac)-tert-butyl ((1R,3S)-3-((8-iodo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509a, 1.49 g, 3.30 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 1.331 g, 3.96 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium (II) (0.117 g, 0.165 mmol), and potassium phosphate (2.102 g, 9.90 mmol) in 1,4-dioxane (26.4 mL)/water (6.60 mL) was sparged with nitrogen for 3 min at RT; the red reaction mixture was then heated to 80° C. for 1 h. More (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.33 g) was added, and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (150 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (3×100 mL); the aqueous layer was extracted with EtOAc (4×100); the organic layers were separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-8% 2 M ammonia in MeOH/DCM to give (rac)-tert-butyl ((cis)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509, 0.59 g, 0.582 mmol, 17% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.34 (m, 3H) 1.37 (s, 9H) 1.40 (d, J=6.65 Hz, 3H) 1.42-1.54 (m, 2H) 1.73-1.89 (m, 2H) 1.99-2.20 (m, 2H) 3.44 (s, 3H) 3.92-4.11 (m, 1H) 4.48-4.59 (m, 0.5; H) 4.60-4.74 (m, 0.5; H) 6.79-6.99 (m, 3H) 7.15 (t, J=7.73 Hz, 1H) 7.63 (d, J=4.30 Hz, 1H) 7.82 (d, J=7.04 Hz, 1H) 7.97 (dd, J=11.54, 7.82 Hz, 1H) 11.99 (br. s., 0.4; H) 12.09 (br. s., 0.6; H). MS (ESI, pos. ion) m/z: 507.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:24][C:25]([NH:27][CH3:28])=[O:26].C(N(CC)CC)C.[Na+].[I-]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:22][CH2:24][C:25]([NH:27][CH3:28])=[O:26])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Reactant: CNC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CNC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 80 °C
Yield: 51 %

Procedure:
To a solution of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine (0.07 g, 0.22 mmol) and 2-chloro-N-methylacetamide (0.023 g, 0.22 mmol) in dry DMF (3 mL) in a sealable tube was added triethylamine (0.1 mL, 0.72 mmol) and NaI (0.01 g). The tube was sealed and heated for four hours at 80° C., then cooled and quenched by addition of water. The reaction mixture was extracted EtOAc, and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography (EtOAc:MeOH 99:1 to 97:3) gave 0.044 g of 2-{[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-amino}-N-methyl-acetamide as a foam. MS (M+H)=393.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:36](I)[CH3:37]>>[Cl:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:21]([N:18]1[CH2:19][CH2:20][N:15]([N:14]([CH2:36][CH3:37])[CH:11]3[CH2:12][CH2:13][N:8]([C:11]4[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=4)[CH2:9][CH2:10]3)[C:16](=[O:35])[CH2:17]1)(=[O:22])=[O:23])[CH:33]=[CH:32]2
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Product: CCN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Yield: 590.5 %

Procedure:
(Method A) Similarly to Method A in Example 38 and using 1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (1.57 g) and ethyl iodide (4.68 g) instead of methyl iodide, the title compound (4.68 g) was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[C:5](=O)[NH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:26])=O>>[Br:1][C:2]1[C:3]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[C:5]([Cl:26])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(Br)c2sc(-c3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1ncc(Br)c2sc(-c3ccccc3)cc12

Procedure:
A mixture of 7-bromo-2-phenyl-5H-thieno[3,2-c]pyridin-4-one 3 (2.28 g, 7.5 mmol) in phosphorus oxychloride (27 mL) was heated at reflux for 21 h. The reaction mixture was basified to pH 5-6 by the addition of saturated aqueous sodium carbonate and extracted with dichloromethane (1×). The organic layer was dried over Na2SO4, filtered, and the filtrate was purified by silica gel column chromatography (eluent: hexane:EtOAc, 97:3) to give 95.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15]>ClCCl>[N:1]1([S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCOCC1
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of morpholine (1.91 g, 22 mmol and triethylamine (2.2 g, 22 mmol) in dichloromethane (100 mL) at 0° C. was added 2-nitrobenzenesulfonyl chloride (4.42 g, 20 mmol). The mixture was stirred for 4 h and then additional dichloromethane (100 mL) was added. The dichloromethane solution was washed with saturated NaHCO3 (2×50 mL), 10% HCl (2×50 mL) and brine (50 mL) and dried over Na2SO4. Evaporating the solvent in vacuo gave the title compound as a yellow solid (5.3 g, 97%). 1H-NMR (300 MHz, CDCl3) δ7.97 (d, J=7.3 Hz, 1H), 7.62-7.77 (m, 3H), 3.75 (t, J=4.7 Hz, 4H), 3.30 (t, J=4.8 Hz, 4H).