Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2C)[N:3]=1.ClC1C=CC(OCC)=[C:22](C=1)[C:23](O)=[O:24]>>[Cl:8][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:24][CH2:23][CH3:22])[N:5]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Reactant: CCOc1ccc(Cl)cc1C(=O)O
Product: CCOc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Yield: 31 %

Procedure:
Using the method described for the synthesis of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine, 5-chloro-2-ethoxybenzoic acid afforded 2,4-dichloro-6-(5-chloro-2-ethoxy-phenyl)-[1,3,5]triazine (9.5 g, 31% yield). 1H NMR (DMSO-d6) 7.62-7.86 (m, 2H), 7.20-7.31 (m, 1H), 4.20 (m, 2H), 1.37 (m, 3H).
Reaction SMILES: C([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH:10]=[C:9]1[CH3:19])C1C=CC=CC=1.CC([O-])(C)C.[K+].O=O>C1COCC1.CS(C)=O>[CH3:18][O:17][C:12]1[C:11]2[CH:10]=[C:9]([CH3:19])[NH:8][C:16]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1nccc2c1cc(C)n2Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1nccc2[nH]c(C)cc12

Procedure:
To a stirred solution of (1-benzyl-4-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine 2 (0.887 mg, 3.52 mmol) in THF (10 mL), DMSO (2.5 mL), followed by KOtBu (25 mL, 1.0 M in THF) was added dropwise, and then the reaction mixture was treated with O2 for 15 min at room temperature, quenched with saturated NH4Cl (20 mL), extracted with EtOAc (3×60 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over Na2SO4 and evaporated. Flash chromatography of the residue over silica gel, using 20% EtOAc in hexanes to 40% EtOAc in hexanes) gave product 3 as a yellow solid. Yield: 560 mg (98%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C@:3]([OH:9])([CH3:8])[C:4](OC)=[O:5].O.[NH2:13][NH2:14]>>[F:1][C:2]([F:11])([F:10])[C@:3]([OH:9])([CH3:8])[C:4]([NH:13][NH2:14])=[O:5]
Reactant: NN
Reactant: COC(=O)[C@](C)(O)C(F)(F)F
Solvent: O
Product: C[C@](O)(C(=O)NN)C(F)(F)F
Temperature: 130 °C

Procedure:
To a solution of methyl(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (3.26 g, 19.0 mmol) was added hydrazine monohydrate (2.1 ml). The mixture was heated at 130° C. for 90 min and cooled down to room temperature. After evaporation to dryness, the residue was purified on a small bed of silica gel (100% EtOAc) to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.ClCCl.N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:20]([O:1][CH2:2][C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(CO)o1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-hydroxymethylfuran-2-carboxylic acid (5.90g), dry dichloromethane (100ml), pyridine (6.71ml), 4-dimethylaminopyridine (507mg), and acetic anhydride (4.21ml) was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate and washed with 5M hydrochloric acid and brine (3 times), dried (MgSO4), and evaporated. The residue was re-evaporated twice from dry toluene to give the title acid as a solid (5.00g); δH [(CD3)2CO]2.05 (3H, s), 5.11 (2H, s), 6.62 (1H, d, J 4Hz), 7.17 (1H, d, J 4Hz) and 8.31 (1H, br s).
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])(=[O:9])[O:4]CCCC)[CH3:2].Cl>>[CH2:1]([P:3]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])(=[O:4])[OH:9])[CH3:2]
Reactant: CCCCOP(=O)(CC)CCOCC
Agent: Cl
Product: CCOCCP(=O)(O)CC
Temperature: 90 °C
Yield: 93.9 %

Procedure:
In a stirred apparatus, 222 g (1 mol) of butyl ethyl(2-ethoxyethyl)phosphinate (produced as in Example 7) are dissolved in 200 ml (2 mol) of concentrated hydrochloric acid. The efficiently stirred mixture is heated to about 90° C. and reacted at that temperature for about 8 hours. The water is then completely distilled off in vacuo. The residue is taken up in acetic acid and extracted. The solvent of the filtrate is removed in vacuo to obtain 156 g (94% of theory) of ethyl-(2-ethoxyethyl)phosphinic acid as oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([CH2:13][CH2:14][C:15](O)=[O:16])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].B.Cl>O1CCCC1>[OH:16][CH2:15][CH2:14][CH2:13][C:8]12[CH2:9][CH2:10][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:12][CH2:11]1)[CH2:6][CH2:7]2
Reactant: COC(=O)C12CCC(CCC(=O)O)(CC1)CC2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C12CCC(CCCO)(CC1)CC2

Procedure:
Carboxylic acid 11-3 (400 mg, 1.67 mmol) was dissolved in tetrahydrofuran (5 mL) and borane (1 M solution in THF, 2.17 mL, 1.3 eq.) was added dropwise at room temperature. After 2 h the reaction was added to 50 mL of 1 N HCl and then extracted three times with 50 mL of methylene chloride. The combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure to afford crude methyl 4-(3-hydroxypropyl)bicyclo[2.2.2]octane-1-carboxylate (11-4) which was used without purification in the next step. 1H NMR (500 MHz, CD3OD): δ 3.66 (3H, s), 3.62 (2H, t, J=6.5 Hz), 1.78 (6H, m), 1.50 (2H, m), 1.41 (2H, m), 1.17 (2H, m) ppm.
Reaction SMILES: Br[C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:35]=[CH:34][C:10]([CH2:11][N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[C:13]3[C:14]([CH3:24])=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br-].[CH2:39]([O:41][C:42](=[O:47])[CH2:43][CH2:44][CH2:45][Zn+])[CH3:40]>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[CH2:25][N:12]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:36]=[CH:37][C:2]([CH2:45][CH2:44][CH2:43][C:42]([O:41][CH2:39][CH3:40])=[O:47])=[CH:3][CH:4]=2)=[CH:35][CH:34]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:20]([CH3:23])(=[O:21])=[O:22])[C:14]=1[CH3:24]
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2ccc(Br)cc2)cc1)Cc1ccc(F)cc1F
Reactant: CCOC(=O)CCC[Zn+]
Agent: [Br-]
Product: CCOC(=O)CCCc1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1

Procedure:
The product from Example 48B and 4-ethoxy-4-oxobutylzinc bromide (purchased from Aldrich) were processed as described in Example 49 to provide the title compound. MS (ESI+) m/z 623 (M+H)+.
Reaction SMILES: C(P(CCCC)CCCC)CCC.CN(C(/N=N/C(N(C)C)=O)=O)C.C([O:29][C:30]1[C:35]([CH3:36])=[C:34]([C:37]2[O:38][C:39]3[CH:45]=[CH:44][C:43](O)=[CH:42][C:40]=3[CH:41]=2)[O:33][C:32](=[O:47])[C:31]=1[CH3:48])(=O)C.[OH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[N:55][CH:56]=1.[OH-].[Li+].Cl>C1COCC1.C(Cl)Cl.CCOC(C)=O>[CH3:48][C:31]1[C:32](=[O:47])[O:33][C:34]([C:37]2[O:38][C:39]3[CH:45]=[CH:44][C:43]([O:49][CH2:50][C:51]4[CH:52]=[N:53][CH:54]=[N:55][CH:56]=4)=[CH:42][C:40]=3[CH:41]=2)=[C:35]([CH3:36])[C:30]=1[OH:29]
Reactant: OCc1cncnc1
Reactant: CC(=O)Oc1c(C)c(-c2cc3cc(O)ccc3o2)oc(=O)c1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cc3cc(OCc4cncnc4)ccc3o2)oc(=O)c(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tributylphosphine in 2 N THF (0.94 ml) and a solution of TMAD (323 mg) in CH2Cl2 (3 ml) were added dropwise to a solution of 4-acetyloxy-3,5-dimethyl-6-(5-hydroxybenzofuran-2-yl)-2H-pyran-2-one (118 mg) and 5-hydroxymethylpyrimidine (202 mg) in THF (30 ml) at 0° C., and the mixture was stirred at room temperature overnight. The reaction solution was cooled on ice, a 1 N lithium hydroxide aqueous solution (5 ml) was added and the mixture was stirred at room temperature for one hour, after which the reaction solution was again cooled on ice, a 1 N hydrochloric acid aqueous solution (5 ml) and AcOEt were added, the organic layer and aqueous layer were separated, and the aqueous layer was further extracted with AcOEt. The organic layers were combined and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (AcOEt/MeOH=10/1) to obtain 3,5-dimethyl-4-hydroxy-6-(5-(5-pyrimidinylmethoxy)benzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=3)=[CH:11][C:10]([C:21]([O:23]CC)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C#N)c2)n(-c2cccc(Cl)c2)n1
Agent: [K+]
Agent: [OH-]
Product: N#Cc1cccc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1
Yield: 94 %

Procedure:
Starting from 2.75 g (7.82 mmol) of ethyl 1-(3-chlorophenyl)-5-(3-cyanophenyl)-1H-pyrazole-3-carboxylate from example 16A and 4.39 g (78.2 mmol) of potassium hydroxide, 2.37 mg (7.3 mmol, 94% yield of theory) are obtained as crystals according to the method described in example 7A.
Reaction SMILES: [CH2:1]([C:5]1([CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[Cl:14])[C:6]1=O)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.Cl.CCOC(C)=O>[CH2:1]([C:5]12[CH2:18][CH2:19][C:20](=[O:23])[C:21]([CH3:22])=[C:6]1[C:7]1[C:12](=[C:11]([Cl:14])[C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCC(=O)CC)Cc2c(ccc(OC)c2Cl)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C(C)=C1c1ccc(OC)c(Cl)c1C2
Temperature: 90 °C
Reaction time: 48 h
Yield: 60.6 %

Procedure:
A solution of 2-butyl-4-chloro-5-methoxy-2-(3-oxo-pentyl)-1-indanone (250 mg, 0.74 mmol) in acetic acid (2 mL) was diluted with 6N aqueous HCl (2 mL). The resulting mixture was stirred and heated in an oil bath at 90° C. for 18 hours, then kept at room temperature for 2 days. The mixture was diluted with EtOAc (20 mL), washed with water (30 mL), 5% NaHCO3 (10 mL) and brine (5 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (250 mg). The crude product was purified by preparative layer chromatography on three 0.1×20×20 silica gel GF plates, developing with 5% EtOAc in CH2Cl2, to afford 9a-butyl-8-chloro-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (143 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:22]([NH2:24])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:34])([F:33])[CH2:27][NH:28][S:29](Cl)(=[O:31])=[O:30].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:22]([NH:24][S:29]([NH:28][CH2:27][C:26]([F:34])([F:33])[F:25])(=[O:31])=[O:30])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC(N)c1cccc(-c2cc(CCc3ccc(F)cc3)n(C)n2)c1
Reactant: O=S(=O)(Cl)NCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NS(=O)(=O)NCC(F)(F)F)c1cccc(-c2cc(CCc3ccc(F)cc3)n(C)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
This amine was dissolved in CH2Cl2 (5 mL) and treated with 2,2,2-trifluoroethylsulfamoyl chloride (91 mg, 0.45 mmol) and Et3N (63 μL, 0.45 mmol) and stirred at RT for 30 min. The solvent was evaporated under reduced pressure and the residue purified by silica chromatography eluting with 2% MeOH/CH2Cl2 to yield the title sulfamide as a colourless gum (18 mg, 23% over 2 steps). 1H NMR (CDCl3, 500 MHz) δ 7.80-7.76 (1H, s), 7.65 (1H, d, J=7.8 Hz), 7.38 (1H, t, J=7.8 Hz), 7.23 (1H, d, J=7.8 Hz), 7.18-7.10 (2H, m), 6.98 (2H, t, J=8.7 Hz), 6.35 (1H, s), 4.66-4.56 (2H, m), 4.38-4.28 (1H, m), 3.69 (3H, s), 3.53-3.42 (1H, m), 3.42-3.30 (1H, m), 3.02-2.84 (4H, m), 1.62-1.52 (3H, m). MS (ES+) C22H24F4N4O2S requires: 484, found: 485 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cccc2[N+](=O)[O-])CC1
Yield: 74.4 %

Procedure:
To a stirred solution of 1.01 g (5.0 mmol) of 1-chloro-2,6-dinitrobenzene and 0.93 g (5.0 mmol) of 1-tert-butyloxycarbonylpiperazine in acetonitrile (5 mL) was added 1.38 g (10 mmol) of K2CO3. The mixture was heated to reflux for 48 h. The solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (100 mL) and 20 mL of H2O. The organic layer was washed with H2O (2×20 mL), dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% EtOAc/hexanes) provided 1.31 g (85%) of 4-(2,6-dinitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester TLC (silica, 20% EtOAc/hexanes): Rf=0.35. 1H NMR (400 MHz, CDCl3): 7.75 (d, J=8.2 Hz, 2H), 7.25 (t, J=8.2 Hz, 1H), 3.30 (m, 4H), 2.95 (m, 2H), 1.44 (s, 9H). B. 1-[4-(2,6-Dinitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol. 4-(2,6-Dinitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (220 mg, 0.63 mmol) was dissolved in 5.0 mL of CH2Cl2 and treated with 3.0 mL of trifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 h before all volatiles were removed. The solid was treated with CH2Cl2 (20 mL) and aqueous KOH (4 N, 10 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The crude oil (67 mg) was dissolved in absolute EtOH (1.2 mL) and treated with 141 mg (0.35 mmol, 1.3 eq) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was refluxed at 85° C. for 3 h and then the solvent was removed. Column chromatography purification (silica, 10-20% acetone/CH2Cl2) provided 150 mg (85%) of 1-[4-(2,6-dinitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol. TLC (silica, 10% acetone/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C27H30F3N7O7S, 653.19; m/z found, 654.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.71 (d, J=8.2 Hz, 2H), 7.64 and 7.58 (AB pattern, J=8.4 Hz, 4H), 7.20 (t, J=8.2 Hz, 1H), 4.54 (s, 2H), 4.29-4.12 (m, 2H), 3.66 (t, J=5.3 Hz, 2H), 3.70-2.95 (m, 9H), 2.91 (s, 3H), 2.67-2.32 (m, 4H).
Reaction SMILES: [Si]([O:8][C:9]([CH3:40])([CH3:39])[CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:37]=[CH:36][C:19]3[C:20]4[N:21]([CH:25]=[C:26]([C:28]5[N:32]([CH:33]([CH3:35])[CH3:34])[N:31]=[CH:30][N:29]=5)[N:27]=4)[CH2:22][CH2:23][O:24][C:18]=3[CH:17]=2)[N:13]=[C:12]1[CH3:38])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:33]([N:32]1[C:28]([C:26]2[N:27]=[C:20]3[C:19]4[CH:36]=[CH:37][C:16]([C:14]5[N:13]=[C:12]([CH3:38])[N:11]([CH2:10][C:9]([CH3:40])([OH:8])[CH3:39])[CH:15]=5)=[CH:17][C:18]=4[O:24][CH2:23][CH2:22][N:21]3[CH:25]=2)=[N:29][CH:30]=[N:31]1)([CH3:35])[CH3:34]
Reactant: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CC(C)(C)O
Temperature: 25 °C
Yield: 34.2 %

Procedure:
9-(1-(2-(tert-Butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-1H-imidazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (110 mg, 0.196 mmol) was dissolved in 5 mL of THF, tetrabutylammonium fluoride (TBAF, 102 mg, 0.392 mmol) was added at 0° C. The temperature was allowed to warm up to room temperature slowly and stirred at room temperature for over night. Concentrated, the residue was portioned with EtOAc-water to give 30 mg of 265. Yield=36%. 1H NMR (CDCl3, 400 MHz): δ8.48 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.64 (s, 1H), 7.51-7.47 (m, 2H), 7.26 (s, 1H), 6.03-5.99 (m, 1H), 4.51-4.43 (m, 4H), 3.85 (s, 1H), 2.47 (s, 3H), 1.65-1.56 (m, 6H), 1.28-1.26 (m, 6H). LC-MS: m/z=433 [M+H+]
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[CH3:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:42]([CH3:43])=[C:21]([NH:20][C:7]([C:6]5[CH:5]=[C:4]([CH3:10])[S:3][C:2]=5[CH3:1])=[O:9])[CH:22]=4)=[CH:30][N:29]3[N:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cc1cc(C(=O)O)c(C)s1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)c(C)s1
Yield: 74.4 %

Procedure:
In the same manner as in Example 55 and using 2,5-dimethylthiophene-3-carboxylic acid (71.0 mg, 0.454 mmol), tetrahydrofuran (5 mL), thionyl chloride (77.0 μL, 0.888 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (129 mg, 0.399 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (137 mg, 74%) was obtained as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:30](Cl)=[O:31])[CH2:24][CH2:23]1>C(Cl)Cl.C(N(CC)CC)C>[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([C:30]([NH:1][CH:2]3[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]3[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[O:31])[CH:33]=[CH:34][C:35]=2[O:36][CH2:37][CH:38]2[CH2:39][CH2:40]2)[CH2:24][CH2:23]1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC
Reactant: O=C(Cl)c1ccc(OCC2CC2)c(OCC2CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2CC(OC(C)=O)CCC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
9.5 mmol of (±)-acetic acid (1SR,3RS,4RS)-4-amino-3-(3,4-dimethoxyphenyl)cyclohexyl ester (compound B2) are dissolved in a mixture of 40 ml of methylene chloride and 10 ml of triethylamine and treated with 8.9 mmol of 3,4-dicyclopropylmethoxybenzoyl chloride. After stirring for 1 h at room temperature, the reaction mixture is concentrated and the residue chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 4/4/1 as eluent. After concentration of the corresponding eluate fractions, 1.86 mmol of the title compound are obtained.
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[C@H:10]([OH:11])[C:9]([CH3:13])([CH3:12])[O:8][C:7]2[CH:14]=[CH:15][C:16]([N+:18]([O-])=O)=[CH:17][C:6]1=2)([CH3:3])[CH3:2].C(OCC)C.[S:26](=O)(=[O:29])([OH:28])[OH:27]>C(O)C.Cl>[S:26]([O:11][C@@H:10]1[C:9]([CH3:13])([CH3:12])[O:8][C:7]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:6]=2[C@H:5]1[NH:4][CH:1]([CH3:3])[CH3:2])([OH:29])(=[O:28])=[O:27]
Reactant: O=S(=O)(O)O
Reactant: CC(C)N[C@@H]1c2cc([N+](=O)[O-])ccc2OC(C)(C)[C@H]1O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CC(C)N[C@@H]1c2cc(N)ccc2OC(C)(C)[C@H]1OS(=O)(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trans-4-Isopropylamino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol (3.54 g.) was added to a solution of stannous chloride (7.90 g.) in ethanol (36 ml.) and concentrated hydrochloric acid (60 ml.) and stirred for 3 hours at ambient temperature. After dilution, work-up via diethyl ether gave a gum (3.25 g.). Purification of this gum (2.00 g.) by application to silica gel plates and development with ethyl acetate/60°-80° petroleum ether mixture gave an amorphous solid (1.01 g.) which was dissolved in dilute sulphuric acid and evaporated to dryness to yield trans-4-isopropylamino-3,4-dihydro-2,2-dimethyl-6-amino-2H-benzo[b]pyran-3-ol sulphate as a light brown solid m.p. 180° - 190°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32](Cl)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:1][C:2]4[CH:10]=[CH:9][C:5]([C:6](=[O:7])[NH2:8])=[CH:4][CH:3]=4)=[C:27]3[CH:26]=[N:25]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C(N)=O)cc4)ncnc32)CC1
Temperature: 160 °C
Yield: 17.9 %

Procedure:
A mixture of 4-hydroxy-benzamide (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 13 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-carbamoyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (7 mg, 18%) as a white solid. Mass spectrum MH+=439.
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.CC1(C)C(C)(C)OB([C:46]2[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]3[C:56](=[O:70])[N:57]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=4)[CH:58]=[CH:59][CH:60]=3)=[O:54])=[CH:48][CH:47]=2)O1.[B].[N:73]1[CH:78]=[CH:77][N:76]=[C:75]2[NH:79][CH:80]=[CH:81][C:74]=12>>[N:73]1[CH:78]=[CH:77][N:76]=[C:75]2[NH:79][CH:80]=[C:81]([C:46]3[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]4[C:56](=[O:70])[N:57]([CH2:61][C:62]5[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=5)[CH:58]=[CH:59][CH:60]=4)=[O:54])=[CH:48][CH:47]=3)[C:74]=12
Reactant: c1cnc2[nH]ccc2n1
Reactant: CC1(C)OB(c2ccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)s2)OC1(C)C
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1ccc(-c2c[nH]c3nccnc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-thiophen-2-ylmethyl]-amide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide) using 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophen-2-ylmethyl]-amide as activated boron species and 5H-Pyrrolo[2,3-b]pyrazine as substituted bicyclic heterocycle, to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.269 (s, 1H) 10.059 (t, J=5.8 Hz, 1H) 8.472 (d, J=2.5 Hz, 1H) 8.404 (dd, J=7.2, 2.2 Hz, 1H) 8.299 (d, J=2.8 Hz, 1H) 8.256-8.214 (m, 2H) 7.497 (d, J=3.6 Hz, 1H) 7.471-7.347 (m, 2H) 7.182-7.127 (m, 1H) 6.993 (d, J=3.6 Hz, 1H) 6.598 (t, J=6.7 Hz, 1H) 5.193 (s, 2H) 4.678 (d, J=5.8 Hz, 2H; MS m/z=478.09 M+H.