Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([O-:30])=[O:29])[N:26]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[N:26]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Sc2nc(CC(=O)[O-])cs2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Sc2nc(CC(=O)O)cs2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of ethyl [2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-thiazolylacetate (330 mg), lithium hydroxide hydrate (89.0 mg), tetrahydrofuran (3 ml), water (2 ml) and methanol (2 ml) was stirred at room temperature for 4 hrs. 1N Hydrochloric acid (2.2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give [2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-thiazolyl]acetic acid (215 mg, yield 69%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 180–181° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:23]([O:22][C:20](=[O:21])[C:19]([O:17][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][C:13]=1[CH:14]=[O:15])([CH3:26])[CH3:25])[CH3:24]
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C=O
Yield: 82.8 %

Procedure:
5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj, T. Arch. Pharm., 1975, 308 (5), 339-346) (169 g, 741 mmol), ethyl bromoisobutyrate (164 mL, 1.11 mol), and cesium carbonate (240 g, 741 mmol) in dry DMF (600 mL) were heated at 80° C. for 15 h. Additional cesium carbonate (5 g) and ethyl bromoisobutyrate (20 mL) were added, and the reaction mixture was heated for 6 h. The reaction mixture was cooled, diluted with EtOAc (4 L), and washed with water (3×2 L). The organic layer was dried (Na2SO4) and concentrated to a brown oil. The crude product was recrystallized from EtOAc (150 mL) with hexanes until turbid to give the title compound as a pale yellow solid (210 g, 83%): mp 65° C.; 1H NMR (400 MHz, CDCl3) δ 1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q, 2H, J=7.1 Hz), 6.81 (d, 1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0 Hz), 7.30-7.43 (m, 6H); MS (ES) m/e 343.1 [M+1].
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[O:23]1[C:28]2=[CH:29][N:30]=[C:31]([CH:33]=O)[CH:32]=[C:27]2[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(Cl)(Cl)[Cl:55]>CO>[ClH:55].[O:23]1[C:28]2=[CH:29][N:30]=[C:31]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[CH:32]=[C:27]2[CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: ClC(Cl)Cl
Reactant: O=Cc1cc2c(cn1)OCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)OCCC3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of (2R)-2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j)) (60 mg, 0.199 mmol) and 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)) (29.2 mg, 0.179 mmol) in chloroform (2 ml) and methanol (0.061 ml) at rt under nitrogen was treated with sodium triacetoxyborohydride (127 mg, 0.597 mmol) and stirred at rt for 30 min. The reaction was then treated with saturated aqueous NaHCO3 (10 ml) and extracted with 20% methanol/DCM (3×20 ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and purified using silica chromatography (0-20% MeOH/DCM) to give the free base of the title compound as a light brown solid
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].Cl[C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19][C:18]=1[C:24]#[N:25]>C1COCC1.CCOC(C)=O>[Cl:23][C:21]1[CH:22]=[C:17]([NH:3][C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[C:18]([C:24]#[N:25])=[CH:19][N:20]=1
Reactant: CON(C)C(=O)c1ccccc1N
Reactant: N#Cc1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccccc1Nc1cc(Cl)ncc1C#N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 34.2 %

Procedure:
Sodium hydride (0.888 g, 22.20 mmol) was added portionwise to a mixture of 2-amino-N-methoxy-N-methylbenzamide (1.00 g, 5.55 mmol), in THF (30 mL) cooled to 0° C. under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 20 minutes and then 4,6-dichloropyridine-3-carbonitrile (0.960 g, 5.55 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (50 mL). The mixture was washed sequentially with water (50 mL), a saturated solution of NaHCO3 (50 mL), water (25 mL) and finally with a saturated solution of NaCl (20 mL). The organic layer was dried over Na2SO4 and then evaporated. The residue was crystallised from Et2O/MeOH to afford 2-[(2-chloro-5-cyanopyridin-4-yl)amino]-N-methoxy-N-methylbenzamide (0.602 g, 34% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.15 (3H, s), 3.47 (3H, s), 6.56 (1H, s), 7.39-7.44 (2H, m), 7.52-7.56 (2H, m), 8.45 (1H, s), 9.33 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=317.28 and 319.30.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[N:13][CH:14]=2)=[C:4]([F:19])[C:3]=1[CH:20]1[CH2:24][CH2:23][CH2:22][O:21]1.O1CCOCC1.[CH2:31]([NH:33][C:34]([NH:36][C:37](SC)=NC(=O)NCC)=[O:35])[CH3:32].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH2:31]([NH:33][C:34]([NH:36][C:37]1[NH:1][C:2]2[C:3]([CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)=[C:4]([F:19])[C:5]([C:9]3[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:16])[CH3:17])=[N:13][CH:14]=3)=[CH:6][C:7]=2[N:8]=1)=[O:35])[CH3:32]
Reactant: CC(C)(O)c1ncc(-c2cc(N)c(N)c(C3CCCO3)c2F)cn1
Reactant: CCNC(=O)N=C(NC(=O)NCC)SC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c(C3CCCO3)c2[nH]1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a stirring suspension of 2-[5-(4,5-diamino-2-fluoro-3-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (21) (111.3 g, 334.9 mmol) and 1,4-dioxane (556.5 mL, Sigma-Aldrich 360481) was added 1-ethyl-3-(N-(ethylcarbamoyl)-C-methylsulfanyl-carbonimidoyl)urea (10) (93.36 g, 401.9 mmol, CB Research and Development) followed by a pH 3.5 buffer (1.113 L), prepared by dissolving NaOAc trihydrate (158.1 g) in 1N aqueous H2SO4 (1.100 L). The reaction mixture was stirred at reflux overnight (HPLC showed complete conversion), cooled to room temperature, and poured portion-wise (frothing) into a stirring solution of aqueous saturated NaHCO3 (2.23 L) giving pH 8-9. This was stirred for 30 minutes, the solid was collected by filtration, washed copiously with water to neutral pH, and then more sparingly with EtOH. The solid was dried under reduced pressure giving 22 as an off-white yellowish solid (135.2 g, 94% yield; 99% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 429.58 (2.03 min). 1H NMR (300 MHz, MeOD) δ 8.95 (d, J=1.6 Hz, 2H), 7.45 (d, J=6.5 Hz, 1H), 5.38 (br.s, 1H), 4.27 (dd, J=14.9, 7.1 Hz, 1H), 4.01 (dd, J=15.1, 7.0 Hz, 1H), 3.37-3.29 (m, 2H), 2.55 (br.s, 1H), 2.19-2.07 (m, 2H), 2.02-1.82 (br.s, 1H), 1.63 (s, 6H), 1.21 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][C:32]=2[CH:33]=1)[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:34][C:32]=2[C:33]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C(O)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(Cl)cc1

Procedure:
4.02 g of 4-chlorobenzoyl chloride—prepared by reacting 4-chlorobenzoic acid with thionyl chloride—and 5.42 g of 2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml of dichloromethane. The reaction was performed according to Example 10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[CH:26]1([C:29]([CH3:31])=O)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:29]([CH:26]3[CH2:28][CH2:27]3)[CH3:31])[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CC(=O)C1CC1
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C(C)C3CC3)CC2)nc1
Product: Cl
Temperature: 50 °C
Reaction time: 48 h
Yield: 93.2 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess cyclopropylmethyl ketone (1.24 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 48 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-2 M ammonia in methanol afforded 0.27 g of impure free-base product. Subsequent purification by reverse phase HPLC provided 34 mg of the pure title hydrochloride as a yellow solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[C:5](=[O:13])[O:4][C:3]=1[CH:14]([OH:16])[CH3:15].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:13])[O:4][C:3]([CH:14]([OH:16])[CH3:15])=[C:2]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(O)c1oc(=O)c2ccc(Cl)cc2c1Br
Reactant: OB(O)c1ccccc1
Product: CC(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Yield: 44.6 %

Procedure:
The title compound was made in a similar way of that of Intermediate B53 from 4-bromo-6-chloro-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A6, 0.973 g, 3.205 mmol) and phenylboronic acid (0.586 g, 4.808 mmol) to yield title compound as a white foam (0.430 g, 1.43 mmol, 45%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[N:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][NH:37][CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)[C:20]([CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:19][C:18]=1[OH:46]>>[CH2:2]([NH:1][CH2:6][CH3:5])[CH3:3].[F:16][C:17]1[C:18]([OH:46])=[CH:19][C:20]([CH2:41][C:42]([F:43])([F:44])[F:45])=[C:21]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][N:37]([C:13]([C:10]6[CH:9]=[N:8][C:7]([N:1]7[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]7)=[CH:12][N:11]=6)=[O:15])[CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)[CH:22]=1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Reactant: O=C(O)c1cnc(N2CCCCC2)cn1
Product: CCNCC
Product: O=C(c1cnc(N2CCCCC2)cn1)N1CCc2[nH]c(-c3n[nH]c4cc(-c5cc(F)c(O)cc5CC(F)(F)F)ccc34)nc2C1
Yield: 49.8 %

Procedure:
The title compound was prepared from 5-piperidin-1-yl-pyrazine-2-carboxylic acid (Preparation 44, 35 mg, 168 μmol) and 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (Preparation 39, 100 mg, 168 μmol) using the method of Example 8. The crude material was purified by HPLC Method A to afford 29.0 mg of the title compound as the diethylamine salt.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C[N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([OH:13])=[O:12].[CH3:14]C(OC(C)=O)=O>>[CH3:14][C:8]1[C:9]([N+:1]([O-:4])=[O:2])=[CH:10][NH:6][C:7]=1[C:11]([OH:13])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Reactant: Cn1cccc1C(=O)O
Product: Cc1c([N+](=O)[O-])c[nH]c1C(=O)O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (8 mL) was treated with 70% nitric acid (1.6 mL) and the mixture heated to 50° C. for 15 minutes, then cooled to room temperature, and slowly added to a suspension of 1-methyl-2-pyrrolecarboxylic acid (2 g) in Ac2O (12 mL) and cooled to −25° C. The mixture was stirred at −15° C. for 0.5 hr, then the temperature was allowed to rise to ambient, and stirring was continued for 20 min. The mixture was again cooled to −25° C. and the resulting precipitate was collected in a funnel cooled on dry ice. The solid was washed with a small amount of cold Ac2O (−25° C.), and then dissolved in 1M NaOH solution. Acidification with 1M HCl precipitated the compound. Yield (0.77 g, 28%). 1H NMR (DMSO): δ 8.19 (d, 1H, J=1.8 Hz); 7.23 (d, 1H, J=2.0 Hz); 3.90 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:12])[NH:6]2.N1C=CC=CC=1.[C:19]1([CH3:36])[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:35][CH2:34][CH2:33][C@H:29]2[C:30](O)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=1.S(Cl)(Cl)=O>C(Cl)Cl>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C@H:5]([CH3:12])[N:6]2[C:30](=[O:31])[C@@H:29]1[CH2:33][CH2:34][CH2:35][N:28]1[S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:36])=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CC1Cc2c(ccc(F)c2F)N1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N2c3ccc(F)c(F)c3C[C@@H]2C)cc1
Reaction time: 1.5 h

Procedure:
(±)-4,5-difluoro-2-methyl-2,3-dihydroindole, 47.4 g, was dissolved in 470 ml of methylene chloride, to which was added 45 ml of pyridine under ice-cooling. To the resultant mixture was added dropwise under ice-cooling 300 ml of a methylene chloride a solution of the acid chloride prepared from 98.8 g of (S)-N-p-toluenesulfonyl proline and 80 ml of thionyl chloride. After the dropwise addition, the reaction was conducted for 1.5 hours at room temperature. The reaction mixture was washed with 750 ml of 10% hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate, and with a saturated aqueous solution of sodium chloride, in this order, and dried over anhydrous magnesium sulfate. Methylene chloride was evaporated off, the residue was washed with ether, with benzene and with ethanol, in this order. All of the washings were combined and concentrated, and the residue was subjected to column chromatography on 3 kg of silica gel with elution with benzene-ethyl acetate (30:1-15:1), to give a main product and a by-product. The main product was recrystallized from isopropanol-benzene, to give 51.8 g of (-)-4,5-difluoro-2-(S)-methyl-1-[(S)-N-p-tol uenesulfonylprolyl]-2,3-dihydroindole (Compound (a)) having the following physical characteristics.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.C[O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]3[CH:38]=[CH:37][C:36]([C:39]4([CH3:44])OCC[O:40]4)=[CH:35][C:29]=3[C:30](=O)[O:31]2)=[CH:26][CH:25]=1.[Li]>C1COCC1.O>[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]3[CH:38]=[CH:37][C:36]([C:39](=[O:40])[CH3:44])=[CH:35][C:29]=3[CH:30]([C:2]3[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=3)[O:31]2)=[CH:26][CH:25]=1
Reactant: COc1ccc2c(c1)oc(=O)c1cc(C3(C)OCCO3)ccc12
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)Oc1cc(O)ccc1-2
Temperature: -78 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
1-[2-(4-bromo-phenoxy)-ethyl]-piperidine (0.76 g, 2.7 mmol) from Step F was dissolved in THF (15 ml) under Ar and cooled to −78° C. n-Butyl lithium (10.0 M, 0.26 ml, 2.6 mmol) was added and the mixture was stirred at −78° C. for 1 hour. The compound from Step E (1.11 g, 3.56 mmol) was dissolved in THF (35 ml) under Ar and cooled to −78° C. to which the freshly prepared lithium salt of 1-(2-(4-bromo-phenoxy)-ethyl)-piperidine was transferred via a cannula. The reaction was stirred for 2 h. Water (150 ml) was added and the reaction extracted three times with ethyl acetate (150 ml). After removing the solvent the crude product was chromatographed on silica gel with 7% CH3OH/CH2Cl2 to yield 0.56 g (48%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 1.44 (2H, m, NCH2CH2CH2), 1.59 (4H, m, NCH2CH2CH2) 1.61 (3H, s, CH3), 2.25 (4H, m, NCH2CH2CH2), 2.83 (2H, m, NCH2CH2O), 3.78 (2H, m, OCH2), 3.85 (3H, s, OCH3), 4.01 (2H, m, OCH2), 4.18 (2H, m, NCH2CH2O), 6.69 (1H, s, ArH), 6.73 (1H, d, ArH), 6.96 (2H, d, ArH), 7.17 (1H, s, ArH), 7.56 (1H, m, ArH), 7.60 (2H, d, ArH), 7.76 (2H, m, ArH).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH:10]=O)=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[NH:12]([CH2:19][CH2:20][C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[NH:12]([CH:19]=[C:20]([CH2:10][C:7]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9][CH:8]=1)[C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1csc2ccccc12
Reactant: N#CCCNc1ccccc1
Solvent: O
Product: N#CC(=CNc1ccccc1)Cc1csc2ccccc12

Procedure:
The title compound was prepared from thianaphthene-3-carboxaldehyde (W. J. King and F. F. Nord, J. Org. Chem. 1948, 13, 635) and 3-anilinopropionitrile by the procedure of Example 4A (29%); mp 168°-170° dec. Anal. Calcd for C18H14N2S: 0.1 H2O: C, 73.99; H, 4.90; N, 9.59; S, 10.97. Found: C, 74.03; H, 5.21; N, 9.59; S, 11.01.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]([OH:6])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:19][C:20]1[N:21]=[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:45])=[C:33]([NH:35][C:36]([C:38]4[N:42]([CH3:43])[N:41]=[C:40]([CH3:44])[CH:39]=4)=[O:37])[CH:34]=3)=[N:24][N:23]2[CH:46]=1>CN(C)C=O.CN(C)C(=O)C>[CH3:43][N:42]1[C:38]([C:36]([NH:35][C:33]2[CH:34]=[C:29]([O:28][C:25]3[CH:26]=[CH:27][C:22]4[N:23]([CH:46]=[C:20]([NH:19][C:4]([CH:2]5[CH2:3][O:1]5)=[O:6])[N:21]=4)[N:24]=3)[CH:30]=[CH:31][C:32]=2[CH3:45])=[O:37])=[CH:39][C:40]([CH3:44])=[N:41]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: O=C(O)C1CO1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CO5)cn4n3)ccc2C)n(C)n1
Yield: 52.3 %

Procedure:
In the same manner as in Example 279 and using oxirane-2-carboxylic acid (54 mg, 0.62 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (53 μL, 0.62 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (170 mg, 0.41 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (96 mg, 52%) was obtained as a white solid.
Reaction SMILES: C(N)C1C=CC=CC=1.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:27][O:28][C:29]1[C:34]([O:35][CH2:36][CH2:37][N:38]([CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]2[C:55]3[C:56]4[C:61]([NH:62][C:54]=3[CH:53]=[CH:52][CH:51]=2)=[CH:60][CH:59]=[CH:58][CH:57]=4)CC2C=CC=CC=2)=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cl-].[Cl-].[Zn+2].C1OCCOC1>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][NH:38][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[NH:62][C:61]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:55]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Cl-]
Agent: [Zn+2]
Agent: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Solvent: C1COCCO1
Solvent: NCc1ccccc1
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Reaction time: 10 h

Procedure:
To 5 ml Dioxane 1.4 g (0.0054 moles) of anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 0.21 g (0.0015 moles) of anhydrous ZnCl2 and 1 g (0.0042 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 2.5 hrs (TLC control for checking conversion to N-benzyl carvedilol). The dioxane is distilled off from the reaction mixture and to the concentrated mass is added 10 ml ethylacetate, followed by 2 ml of ˜12-15% aqueous ammonia. The aqueous layer separated, and the product enriched organic layer is washed with water till neutral pH. The organic layer is charcoalised, filtered. To this solution of N-benzyl carvedilol in ethylacetate, (0.14 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 3.5-4.5 Kg/cm2 at temperature of 60-70° C. for a period of about 10 hours. The reaction mixture is filtered and filtrate concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (2 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (1 ml) and toluene (1 ml) to obtain carvedilol (0.9 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (0.8 g).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([CH3:11])=[O:10])[CH3:4].N#N>CCO>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:10])[CH2:11][Br:1])[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)CCC(C)=O
Agent: N#N
Solvent: CCO
Product: CCOC(=O)CCC(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (22 g, 7.2 mL, 138.8 mmol) was added to a solution of ethyllevulinate (20 g, 138.8 mmol) in 250 mL EtOH at room temperature under a flow of N2 for a period of 0.5 h. After the addition was complete, the reaction mixture was stirred at room temperature for another 0.5 h, and then refluxed for 1.5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was taken into ether, washed with saturated aqueous NaHCO3 (3×50 mL), water, brine, dried (MgSO4) and concentrated to give 20.3 g of K-13 as a dark brown oil. This was used without purification for next step. 1H NMR.