Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][N:21]=2)=[CH:16][CH2:15]1.[C:29](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH3:29])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][N:21]=2)=[CH:16][CH2:15]1
Reactant: CC(=O)O
Reactant: Fc1ccnc(C2=CCC(c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2C2CC=C(c3cc(F)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
A mixture of (RS)-8-chloro-1-[4-(4-fluoro-pyridin-2-yl)-cyclohex-3-enyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (0.032 g, 0.081 mmol), acetic acid (0.028 ml, 0.49 mmol) and paraformaldehyde (0.010 g, 0.32 mmol) in 1,2-dichloroethane (0.8 ml) was stirred for 16 h at room temperature. Addition of sodium triacetoxyborohydride (0.103 g, 0.49 mmol) was followed by stirring at room temperature for further 3 h. The mixture was partitioned between dichloromethane (50 ml) and 0.5 M aqueous sodium hydroxide solution (50 ml). The layers were separated. The aqueous layer was extracted with one 50 ml-portion of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography with n-heptane/isopropanol as eluent gave the title compound (0.026 g, 79%) as white solid. MS m/e: 410 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11]C(OC(C)(C)C)=O)=[N:9][CH:8]=[C:7]([C:19](=[O:21])[CH3:20])[N:6]=1)=[O:4].Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:19](=[O:21])[CH3:20])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(C(C)=O)cnc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1nc(C(C)=O)cnc1N
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a stirred solution of 6-acetyl-3-tert-butoxycarbonylamino-pyrazine-2-carboxylic acid methyl ester (500 mg, 1.69 mmol) at rt in dioxane (10 ml) under an argon atmosphere was added 4 M HCl solution in dioxane (4.23 ml, 16.9 mmol) in one portion. The reaction mixture was stirred overnight, then concentrated. The residue was triturated with Et2O, filtrated and dried. The solid was taken up in EtOAc (50 ml) and washed with saturated aqueous Na2CO3 solution (20 ml) and brine. The organic phase was dried over MgSO4, filtrated and concentrated to give the title compound (313 mg, 95%) as orange powder.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][O:8][C:9]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:10]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:15][CH:14]=1.CN(C)C.CCOCC>O1CCCC1.O>[C:1]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]=[CH:11][C:10]2[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:9]=2[O:8][CH3:7])=[CH:18][CH:17]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: COc1ccc(OC)c(C=Cc2ccc(OCCCCCCO)cc2)c1
Agent: CN(C)C
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=Cc2cc(OC)ccc2OC)cc1
Temperature: 60 °C
Reaction time: 23 h

Procedure:
Methacryloylchloride 90%, 0.52 ml, 4.8 mmol) was added dropwise To a stirred solution of 6-(2',5'-dimethoxy-4-stilbenoxy)hexanol (14) (1.54 g, 4.32 mmol) and dry trimethylamine (0.76 ml, 5.5 mmol) in dry tetrahydrofuran (25 ml) under argon. The reaction mixture was stirred at 60° C. for 23 h. Ether (200 ml) and water (100 ml) were added. The organic layer was washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane/hexane; 4:1 to 1:0) to yield (15) (1.48 g, 81 %] as an oil; δH (CDCl3) 1.48 (4 H, m, CH2), 1.70 (2 H, m, CH2), 1.80 (2 H, m, CH2), 1.95 (3 H, m, CH3), 3.81 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 3.96 (2 H, J=6.4 Hz, CCH2), 4.16 (2 H, t, J=6.6 Hz, OCH2), 5.55 (1 H, m, HA), 6.10 (1 H, m, HB), 6.76 (1 H, dd, JH4',H3' =8.2 Hz, JH6',H4' =2.9 Hz, H4'), 6.82 (1 H, d, JH4',H3' =8.2 Hz, H3'), 6.87 and 7.46 (4 H, AA'BB', H2, H3, H5, and H6), 7.04 (1 H, d, J=16.5 Hz,. vinytic H), 7.13 (1 H, d, JH4',H6' =2.9 Hz, H6') and 7.32 (1 H, d, J=16.4 Hz, vinylic H); δc (CDCl3) 18.3, 25.69, 25.74, 28.5, 29.1, 53.4, 55.7, 56.2, 64.6, 67.7, 111.3, 112.2, 113.1, 114.5, 120.9, 125.2, 127.5, 127.7, 128.8, 130.4, 136.4, 151.2, 153.7, 158.6 and 167.4.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH2:12]1
Reactant: O=C(O)CCCC1CCCN(C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(CCCCO)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-{[(phenylmethyl)oxy]carbonyl}-3-piperidinyl)butanoic acid (5.01 g, 16.41 mmol) in dry THF (40 ml) at 0° C. under nitrogen was added a solution of Borane-THF complex, (1M soln. in THF) (49.2 ml, 49.2 mmol), dropwise over 1 hour. The mixture was allowed to stir at 0° C. and gradually allowed to warm to rt over 20 hours. The mixture was cooled in an ice bath and cautiously quenched with dropwise addition of MeOH (20 ml) stirred in the cold bath for 2 hours then quenched further with 10% 2N HCl/MeOH (20 ml), stirred for 1 hour at rt and evaporated under reduced pressure. The residue was co-evaporated with methanol several times.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:24])=[C:21]([CH:23]=3)[NH2:22])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:25]1[CH:29]=[C:28]([CH2:30][C:31](Cl)=[O:32])[S:27][CH:26]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH:22][C:31](=[O:32])[CH2:30][C:28]4[S:27][CH:26]=[CH:25][CH:29]=4)[CH:23]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F
Product: O=C(Cc1cccs1)Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F
Yield: 92.5 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluoroaniline (690 mg, 2.0 mmol) and thiophene-2-acetyl chloride (0.26 mL, 2.1 mmol) were coupled according to the procedure of Example 56, Step G to give the desired product (858 mg, 92%). 1H NMR (400 MHz, d6-DMSO) δ 10.21 (s, 1H), 8.93 (d, J=9.2 Hz, 1H), 8.49 (d, J=7.6 Hz, 1H), 8.44 (d, J=12.0 Hz, 1H), 8.29-8.27 (m, 1H), 7.70-7.65 (m, 1H), 7.49-7.41 (m, 3H), 7.27-7.22 (m, 1H), 7.13 (d, J=7.2 Hz, 1H), 7.02-6.98 (m, 2H), 4.02 (s, 2H) ppm.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][C:20]#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.ClC[CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][CH2:39][N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Reactant: ClCCN1CCCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)pyrrolidine
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[NH2:37][CH:38]1[C:44](=[O:45])[NH:43][C:42]2[CH:46]=[CH:47][C:48]3[C:53]([C:41]=2[CH2:40][CH2:39]1)=[CH:52][CH:51]=[CH:50][CH:49]=3>CN(C=O)C.C(OCC)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11](=[O:13])[NH:37][CH:38]1[C:44](=[O:45])[NH:43][C:42]2[CH:46]=[CH:47][C:48]3[C:53]([C:41]=2[CH2:40][CH2:39]1)=[CH:52][CH:51]=[CH:50][CH:49]=3)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2c(ccc3ccccc23)NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)(CC(=O)NC1CCc2c(ccc3ccccc23)NC1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.7 %

Procedure:
A solution of 3-tert-butyloxycarbonylamino-3-methylbutanoic acid (2.43 g, 11.2 mmol) and 1-hydroxybenzotriazole (1.52 g, 11.3 mmol) in DMF (30 ml) was placed under an atmosphere of nitrogen. EDAC (2.19 g, 11.4 mmol) was added and the reaction mixture was stirred for 10 minutes at room temperature. Unresolved 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]- azepine (2.3 g, 10.2 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water (200 ml) and the solution was extracted with dichloromethane (2×250 ml). The combined organic extracts were washed with 10% sodium bicarbonate (2×150 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give a solid residue which was suspended in diethyl ether. Filtration and drying afforded 4.5 g of (1,1-dimethyl -2-(4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepin-3-ylcarbamoyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]([O:12]CC1C=CC=CC=1)=O.[CH3:20][CH2:21][Mg+].[Br-]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([OH:12])[CH2:21][CH2:20]1
Reactant: CC[Mg+]
Reactant: O=C(CCOC1CCCCO1)OCc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: OC1(CCOC2CCCCO2)CC1
Temperature: 18 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a mixture of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate (150 mg, 0.568 mmol) in 2 mL of THF was added Ti(Oi-Pr)4 (0.18 mL, 0.568 mmol, d=0.955 g/L, Ardrich) via a syringe under nitrogen at rt. After stirring at 18° C. for 30 min, EtMgBr (0.48 mL, 1.42 mmol, 3M ether solution, Aldrich) was added via a syringe pump over 2 hrs. The reaction was quenched with 5 mL of water, after benzyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate was consumed completely (monitored by TLC). The mixture was filtered through a celite pad and the filtrate was extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (10:1 (v/v) petroleum ether/EtOAc) to afford 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)cyclopropanol as colorless oil (60 mg, 57%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[NH:13][C:12](=[O:21])[N:11]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:10]2=[O:27])=[O:6].[BH4-].[Na+].Cl>CO.O>[OH:6][CH:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[C:17]([F:18])([F:19])[F:20])[NH:13][C:12](=[O:21])[N:11]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:10]2=[O:27])[CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCC(=O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCC(O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Yield: 94.5 %

Procedure:
A solution of N-[6-(3-methoxy-propionyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (118 mg, 0.288 mmol) in MeOH (3 mL) at r.t. was treated with NaBH4 (77 mg, 2.03 mmol), added portionwise over a period of 3 h. After disappearance of the starting material, the reaction mixture was acidified with 2M aq HCl and diluted with water. The aqueous phase was extracted with EtOAc (2×), the organic phases were combined, washed with brine and dried (Na2SO4) and evaporated. The white powder obtained was purified by MPLC (RP-C18 column (particle size 5-21 μM) with CH3CN/water 1:2. The fractions containing the product were combined, the acetonitrile is distilled off and the residual water phase was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4) and the solvent was removed in vacuo to provide the title compound (112 mg, 94%) as a white powder, mp 180-184° C. 1H-NMR (DMSO-d6, 400 MHz): 11.80 (br s, 1H), 10.35 (br s, 1H), 8.33 (s, 1H), 7.45 (s, 1H), 5.65 (d, J=6 Hz, 1H), 4.98-4.92 (m, 1H), 3.60-3.52 (m, 1H), 3.42-3.35 (m, 1H), 3.20 (s, 3H), 3.15 (s, 3H), 1.86-1.67 (m, 2H).
Reaction SMILES: C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1.Cl.[Cl:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][CH:30]=1.[Cl:35][CH2:36][C:37](=O)[CH2:38][C:39](OCC)=[O:40]>>[Cl:28][C:29]1[S:33][C:32]2=[N:34][C:37]([CH2:36][Cl:35])=[CH:38][C:39](=[O:40])[N:31]2[CH:30]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ncc(Cl)s1
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: Cl
Product: O=c1cc(CCl)nc2sc(Cl)cn12
Yield: 124.1 %

Procedure:
Step 1: This compound was prepared according to the procedure outlined in Intermediate 2, Step 1 using 5-chloro-1,3-thiazol-2-amine hydrochloride (3.01 g, 17.482 mmol) polyphosphoric acid (81.0 g) and ethyl chloroacetoacetate (4.03 g, 24.475 mmol) to afford 5.1 g of the desired compound as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 4.55 (s, 2H), 6.45 (s, 1H), 8.31 (s, 1H); ESI-MS (m/z) 235.57 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[NH:14]1[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2ccncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2ccncc2[nH]1

Procedure:
To a solution of 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (Preparation 14, 310 mg, 1.6 mmol) in ethanol (20 mL) was added 2N sodium hydroxide solution (1 mL, 2.0 mmol) and the reaction mixture heated under reflux for 1.5 h then concentrated in vacuo. The residue was dissolved in water (10 mL) and acidified with acetic acid giving an immediate brown precipitate. The solid was filtered and dried to give the title compound as a beige solid. δH (D2O): 7.11 (1H, s), 7.99 (1H, d), 8.05 (1H, d), 8.85 (1H, s); m/z (ES+)=163 [M+H]+.
Reaction SMILES: C([Li])CCC.[N:6]([CH2:9][CH2:10][C:11]#[CH:12])=[N+:7]=[N-:8].[CH2:13]=[O:14].[Cl-].[NH4+]>C1COCC1>[N:6]([CH2:9][CH2:10][C:11]#[C:12][CH2:13][OH:14])=[N+:7]=[N-:8]
Reactant: C#CCCN=[N+]=[N-]
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCC#CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (1.6 M in hexane, 18.8 mmol, 11.7 ml) was added dropwise at −78° C. to a solution of 4-azido-1-butyne II-32 (1.28 g, 17.3 mmol) in THF (35 ml). After stirring the resulting green solution for 1 h, paraformaldehyde was added in one portion, the solution was stirred for 5 min, and then warmed to room temperature for 2 h (an orange suspension gradually formed). The reaction mixture was poured into saturated aqueous ammonium chloride (100 ml) and extracted with ether (3×50 ml). The combined extracts were washed with brine (50 ml), dried over sodium sulphate and evaporated to give a yellow oil. This was purified by flash chromatography eluting with pentane/ether 1:1 to afford the title compound II-33 as a pale yellow oil (930 mg, 70.7%): IR (CHCl3) 3600 (m), 3000 (m), 2940 (m), 2880 (m), 2100 (s), 1550 (w), 1380 (m), 1270 (m), 1220 (br), 1140 (m), 1000 (s) cm−1; 1H NMR (500 MHz, CDCl3) δ 4.24-4.22 (m, 2H), 3.37 (t, J=6.8 Hz, 2H), 2.51-2.48 (m, 2H), 1.84 (t, J=6.0 Hz, 1H); 13C NMR (62.9 MHz, CDCl3) δ 77.42, 70.47, 49.68, 19.45.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1.O>C(O)(=O)C>[CH3:17][S:14]([NH:13][C:11]1[C:10]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:9][C:6]2[C:7](=[O:8])[C:2]([N:1]3[CH:27]=[CH:31][CH:30]=[CH:29]3)=[CH:3][O:4][C:5]=2[CH:12]=1)(=[O:15])=[O:16]
Reactant: COC1CCC(OC)O1
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc2occ(-n3cccc3)c(=O)c2cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
In 5 ml of acetic acid were dissolved 500 mg of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one and 250 mg of 2,5-dimethoxytetrahydrofuran. The mixture was stirred for 30 minutes at 70°-80° C. and then cooled to room temperature. 50 ml of water was added thereto. The resulting crystal was collected by filtration and recrystallized from ethyl acetate-diisopropyl ether to obtain 250 mg (yield: 43.7%) of 7-methylsulfonylamino-6-phenoxy-3-(1-pyrrolyl)-4H-1-benzopyran-4-one having a melting point of 238.5°-240° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[NH2:15][CH2:16][CH:17]([OH:22])[CH2:18][N:19]([CH3:21])[CH3:20]>>[CH3:20][N:19]([CH3:21])[CH2:18][CH:17]([OH:22])[CH2:16][NH:15][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: CN(C)CC(O)CN
Product: Cc1[nH]c2c(c1C(=O)NCC(O)CN(C)C)CCCC2=O
Yield: 81.8 %

Procedure:
Similar procedure as Example 13, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 1-amino-3-(dimethylamino)propan-2-ol 0.25 g (2.1 mmol) was reacted to give 0.24 g (82%) of the titled compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[N:21]3[N:22]=[CH:23][C:24]([Br:25])=[C:20]3[N:19]=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.S(=O)(=O)(O)O>CO.O1CCOCC1>[Br:25][C:24]1[CH:23]=[N:22][N:21]2[C:16]([NH:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:17][C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[N:19][C:20]=12
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(-c3ccccc3Cl)nc3c(Br)cnn23)CC1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1COCCO1
Product: Clc1ccccc1-c1cc(NCC2CCNCC2)n2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
4-{[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (441 mg, 0.847 mmoles) (prepared as described in Example 460, Step A above) was dissolved in methanol (4.5 mL) and 10% (v/v) conc. sulfuric acid in 1,4-dioxane (11.46 mL) was added. The mixture was stirred at 25° C. for 0.5 h. The product was worked up as described in Preparative Example 241, step B and chromatographed on a silica gel column (15×5 cm) using 8% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give [3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-ylmethylamine (314.4 mg, 88%): FABMS: m/z 420.0 (MH+); HRFABMS: m/z 420.0585 (MH+). Calcd. for C18H20N5BrCl: m/z 420.0591; δH (CDCl3) 1.34 (2H, m, CH2), 1.86 (2H, m, CH2), 1.91 (1H, m, CH), 2.10 (1H, bm, piperidine-NH), 2.67 (2H, m, CH2), 3.18 (2H, m, CH2), 3.38 (2H, m, CH2), 6.37 (1H, s, H6), 6.53 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.06 ppm (1H, s Ar—H); δC (CDCl3) CH2: 31.2, 31.2, 46.2, 46.2, 48.4; CH: 36.4, 89.5, 127.1, 130.1, 130.5, 131.6, 143.8; C: 83.2, 132.1, 138.9, 145.6, 146.4, 158.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([N:26]2[CH2:25][CH2:24][N:23]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=3)[CH2:28][CH2:27]2)[N:12]=1)[CH3:2]
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(N2CCN(c3ccc(Cl)cc3)CC2)n1
Yield: 62.5 %

Procedure:
A mixture of 5.3 g of (4,6-dichloro-2-pyrimidinylthio) acetic acid ethyl ester, 3.9 g of N-(p-chlorophenyl)piperazine and 2.1 g of sodium carbonate in 120 ml. of ethanol was warmed on a steam bath for 10 minutes. The reaction mixture was filtered and the filtrate was diluted with water in order to cause precipitation. The precipitate was recrystallized from ethanol to afford 5.3 g of product, mp. 117°-120°C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.Br[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=1.[Sn].CO>O1CCOCC1.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>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(Br)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Sn]
Solvent: CO
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Yield: 52.1 %

Procedure:
A solution of 408 (1 g, 2.40 mmol) and 6-bromonicotinaldehyde (450 mg, 2.40 mmol) in dioxane (10 mL) was treated sequentially with bistirmethyl tin (500 μL, 787 mg, 2.40 mmol) and Pd(PPh3)4 (270 mg, 0.24 mmol). The reaction mixture was heated to reflux under nitrogen overnight and concentrated. The residue was purified by flash chromatography using the gradient 5%-10% MeOH in DCM as an eluent and subsequent trituration with MeOH, yielding pure 438 (494 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H), 9.10 (m, 1H), 8.65 (d, 1H, J=5.2 Hz), 8.62 (s, 1H), 8.51 (d, 1H, J=8.8 Hz), 8.48 (dd, 1H, J=2.8 Hz, J=10.4 Hz), 8.38 (dd, 1H, J=2.1 Hz, J=8.2 Hz), 8.20 (m, 1H), 7.73 (t, 1H, J=9.0 Hz), 7.01 (d, 1H, J=5.5 Hz). LCMS: (M+H) 395.9.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]=[CH:10][C@H:11]([OH:15])[CH2:12][CH2:13][CH3:14].N1C=CN=C1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Si:1]([O:15][C@H:11]([CH2:12][CH2:13][CH3:14])[CH:10]=[CH2:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C[C@H](O)CCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C[C@@H](CCC)O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
3.8 g (24 mmol) of tert-butyldimethylsilyl chloride were added at −10° C. over the course of 10 minutes in 5 portions to a stirred solution of 2.05 g (20.5 mmol) of (3R)-1-hexen-3-ol and 3.4 g (49 mmol) of imidazole in 50 ml of dry dimethylformamide. After 3 hours at 0° C., the reaction mixture was poured into 200 ml of saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted three. times with 50 ml of n-hexane in each case. The combined organic phases were washed with water and concentrated sodium chloride solution. After drying over anhydrous sodium sulfate and removing the solvent, the residue was chromatographed on 300 g of silica gel. The eluent used was a mixture of 5% by volume ethyl acetate in n-hexane. (3R)-3-(tert-butyldimethylsilyloxy)-1-hexene was obtained as a colorless oil in 91.6% yield ([α]D19=−5.3° (c=2.4 in trichloromethane)).