Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:16]=2)=[C:5]([CH:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])[N:4]([CH3:27])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)OB([C:40]2[CH2:45][CH2:44][CH2:43][C:42](=[O:46])[CH:41]=2)OC1(C)C.C(N(CC)CC)C.ClC(OC)=O>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O.C(O)C>[C:23]([O:22][CH:17]([C:5]1[N:4]([CH3:27])[N:3]=[C:2]([C:40]2[CH2:45][CH2:44][CH2:43][C:42](=[O:46])[CH:41]=2)[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:16]=1)[C:18]([O:20][CH3:21])=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(Br)nn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(C2=CC(=O)CCC2)nn1C
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 60.7 %

Procedure:
A solution of methyl 2-[3-bromo-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]-2-(tert-butoxy)acetate (11i) (100 mg, 0.229 mmol), disodium carbonate (73 mg, 0.686 mmol), and 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (43b) (51 mg, 0.229 mmol) in a mixture of dimethoxyethane (0.87 mL), ethanol (0.37 mL) and water (0.25 mL) was bubbled with nitrogen for 5 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (9.3 mg, 0.011 mmol) was added and the reaction mixture was heated at 140° C. for 2 hours. The solution was concentrated in vacuo. Water (2 mL) was added to the residue and the aqueous layer was washed with diethyl ether (2 mL), acidified with 1M hydrochloric acid until pH 3 and extracted with diethyl ether (2×3 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was dissolved in dichloromethane (1 mL), cooled to 0° C., and under a nitrogen atmosphere, triethylamine (48 μL, 0.343 mmol) and methyl chloroformate (27 μL, 0.343 mmol) were added. The reaction mixture was stirred at 0° C. for 40 minutes and allowed to reach room temperature. Dichloromethane (2 mL) was added, and the mixture was successively washed with 1N hydrochloric acid (2 mL), a saturated solution of sodium hydrogenocarbonate (2 mL), and brine (2 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 70/30) to provide methyl 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(3-oxocyclohex-1-en-1-yl)-1H-pyrazol-5-yl]acetate (43c) (63 mg, 0.139 mmol, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-dichlorobenzoic acid (63 μL, 0.45 mmol) and N,N-dimethyl formamide (DMF) (50 μl) was dissolved in dichloromethane (10 mL). Oxalyl chloride (0.57 mL, 6.7 mmol) was added and the solution stirred at room temperature for 2 hours. The reaction was monitored to completion by LC-MS. The reaction was concentrated in vacuo to afford crude 2,4-dichlorobenzoyl chloride.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:28]([CH3:34])=[N:29][N:30]([CH3:33])[C:31]=2[CH3:32])=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[CH2:35]([O:37][CH2:38]Cl)[CH3:36].Cl>O1CCCC1>[CH2:35]([O:37][CH2:38][N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:14]([F:17])([F:15])[F:16])[C:18]([F:20])([F:21])[F:19])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:28]([CH3:34])=[N:29][N:30]([CH3:33])[C:31]=1[CH3:32])=[O:26])[CH3:36]
Reactant: CCOCCl
Reactant: COC(c1ccc(NC(=O)c2c(C)nn(C)c2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCN(C(=O)c1c(C)nn(C)c1C)c1ccc(C(OC)(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Sodium hydride (29 mg, 60%, 0.73 mmol) was suspended in tetrahydrofuran (10 ml), and a solution of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}-1,3,5-trimethylpyrazole-4-carboxamide (260 mg, 0.48 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at room temperature for 30 min, a solution of chloromethyl ethyl ether (70 mg, 0.73 mmol) in tetrahydrofuran (2 ml) was added, and the mixture was stirred for one day. The reaction mixture was poured into diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to give the desired compound (200 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>>[CH3:20][C:19]1[C:10]([C:8]([C:4]2[CH:3]=[C:2]([CH:27]=[CH:26][C:25]([O:29][CH3:30])=[O:28])[CH:7]=[CH:6][CH:5]=2)=[O:9])=[CH:11][C:12]2[C:13]([CH3:23])([CH3:24])[CH2:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]=2[CH:18]=1
Reactant: C=CC(=O)OC
Reactant: Cc1cc2c(cc1C(=O)c1cccc(I)c1)C(C)(C)CCC2(C)C
Product: COC(=O)C=Cc1cccc(C(=O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
In a manner similar to that of Example 1(c) by reaction of 6.54 g (15 mmol) of 3-iodophenyl-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-methanone with 1.8 ml (19.7 mmol) of methyl acrylate, 6.5 g (100%) of the expected methyl ester are obtained in the form of an orange-coloured oil.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([OH:24])=O)[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN.C[CH2:29][N:30](C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:30][CH3:29])=[O:24])[S:20][CH:21]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(-c1csc(C(=O)O)c1)nn2C1CCCC1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cs1

Procedure:
A solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (75.0 mg), methylamine hydrochloride (22.1 mg), DIEA (0.153 mL), EDCI hydrochloride (62.8 mg) and HOBt (44.3 mg) in DMF (10 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (76.0 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C([O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[N:18][CH:17]=1)C.Cl>C1COCC1.C(OCC)(=O)C.O>[Br:22][C:19]1[N:18]=[CH:17][C:16]([C:15]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:14])=[CH:21][CH:20]=1
Reactant: O=C1CCc2sccc21
Reactant: CCOC(=O)c1ccc(Br)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)nc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 71 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.38 g, 10 mmol) in 30 mL of THF was treated with NaH (60 percent, 0.6 g, 15 mmol). After the addition of 6-Bromo-nicotinic acid ethyl ester (2.3 g, 10 mmol), the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(6-Bromo-pyridine-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.28 g, 7.1 mmol) as red solid in 71% yield.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22][C:23]([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)=O)[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N>CO.C(Cl)Cl>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:14]([C@H:23]([C:25]4[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=4)[CH2:22][N:18]4[CH2:19][CH2:20][CH2:21][C@H:17]43)=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)c1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 54 %

Procedure:
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl-pyrrolidin-1-yl}-1-m-tolyl-ethanone. Prepared as described in Example 8, Step 1, on a 2.70 mmol scale, to give 610 mg (54%) of the desired product as an orange oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C27H36N2O2, 420.3; m/z found, 421.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-c5nnn[nH]5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give, after chromatography on silica gel eluting sequentially with dichloromethane/methanol/concentrated ammonium hydroxide) 95/5/0.1 dichloromethane/methanol/concentrated ammonium hydroxide) 80/20/0.2, the title compound: Rf=0.81 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide) 90/10/0.1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:9]2)=[CH:4][CH:3]=1.CO[C:37](=O)[C:38]1[CH:43]=[C:42]([S:44](=[O:51])(=[O:50])[NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([Cl:52])=[CH:40][C:39]=1[O:53][CH2:54][CH3:55].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[NH:11][C:37]([C:38]3[C:39]([O:53][CH2:54][CH3:55])=[CH:40][C:41]([Cl:52])=[C:42]([S:44]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:51])=[O:50])[CH:43]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C(=O)OC
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Agent: C[Al](C)C
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
In a manner analogous to the method described in example 2, meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) was reacted with 5-tert-butylsulfamoyl-4-chloro-2-ethoxybenzoic acid methyl ester (example 43) in the presence of trimethylaluminum to give the title compound. HR-MS (ES, m/z) calculated for C29H33N3O3SCl3 [(M+H)+] 608.1303, observed 608.1300.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)CC)C.[F:23][C:24]([F:42])([F:41])[C:25]1[CH:40]=[CH:39][C:28]([O:29][CH:30]2[CH2:35][CH2:34][N:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]2)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:41][C:24]([F:23])([F:42])[C:25]1[CH:40]=[CH:39][C:28]([O:29][CH:30]2[CH2:31][CH2:32][N:33]([C:36]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:37])[CH2:34][CH2:35]2)=[CH:27][CH:26]=1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: O=C(Cl)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@](O)(COC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 15.5 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (1.16 g, 4.68 mmol) and triethylamine (1.63 ml, 11.70 mmol) were added to a suspension of 4-(4-trifluoromethylphenoxy)piperidine-1-carbonylchloride (0.72 g, 2.34 mmol) in toluene (40 ml) followed by stirring at 100° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenoxy)-piperidine-1-carboxylate (184 mg, yield 16%) as a colorless oil.
Reaction SMILES: [ClH:1].CO[N:4]=[C:5]1[CH2:24][CH2:23][C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9]2)[CH2:7][CH2:6]1.C(O)(=O)C.[H][H].Cl.CCOCC>CCOCC>[ClH:1].[NH2:4][CH:5]1[CH2:6][CH2:7][C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[O:9]2)[CH2:23][CH2:24]1
Reactant: [H][H]
Reactant: CON=C1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC1CCC2(CC1)OC(C1CCCCC1)c1ccccc12
Yield: 66 %

Procedure:
A mixture of 1.50 of 4-methoxyimino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride, 150 ml of acetic acid and 0.5 g of platinujm oxide is hydrogen at 50 psi and room temperature for 41/2 hours. After filtration and removing the solvent, the oily product is dissolved in 100 ml of dichloromethane and washed with 5% sodium hydroxide solution and water. After drying over anhydrous sodium sulfate, the solvent is removed in vacuo to give an oil. The oil is dissolved in 10 ml of methaol and the solution is made acidic using hydrogen chloride/ether. After addition of 50 ml of ether, the preceipitate is suction filtered, washed with ether and dried to give 66.0% of product, mp 220°-224° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:15]=[CH:14][N:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][N:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.4 %

Procedure:
tert-Butyl 3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionate (0.45 g, 1.2 mmol) was dissolved in trifluoroacetic acid (3.0 ml), and the mixture was stirred at room temperature for 2.5 hrs. Isopropyl ether was added to the reaction mixture to precipitate crystals, which were collected by filtration and washed with ethanol-hexane to give the titled compound (0.32 g, 84%) as white crystals.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][O:29][CH3:30])=[CH:23][CH:22]=3)[N:18]=[C:17]3[N:31]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[N:32]=[C:33]([CH3:34])[C:16]=23)[CH2:10][C@H:9]1[CH2:41][C:42]([F:45])([F:44])[F:43])C1C=CC=CC=1>ClCCl>[CH3:30][O:29][CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:18]=[C:17]3[N:31]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[N:32]=[C:33]([CH3:34])[C:16]3=[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][C@H:9]([CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:10]3)[CH:20]=2)=[CH:22][CH:23]=1
Reactant: COCOc1ccc(-c2cc(CN3CCN(Cc4ccccc4)[C@H](CC(F)(F)F)C3)c3c(C)nn(C4CCCCO4)c3n2)cc1
Solvent: ClCCl
Product: COCOc1ccc(-c2cc(CN3CCN[C@H](CC(F)(F)F)C3)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reaction time: 1.5 h
Yield: 101.3 %

Procedure:
217 mg of 4-[(R)-4-Benzyl-3-(2,2,2-trifluoro-ethyl)-piperazin-1-ylmethyl]-6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine were dissolved in 2.5 ml dichloromethane and 2.5 ml methanol and purged with argon. 22 mg Palladium (10% on charcoal) were added and the mixture was hydrogenated at 5 bar and at r.t. for 1.5 h. The catalyst was filtered off using celite and the solvents were evaporated. 188 mg (100%) of the crude title compound were obtained, which were used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3](=[O:27])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:30]1[C:31]2[C:38]([CH3:39])=[CH:37][NH:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(N(CC)C(C)C)(C)C.C(O)(C)C>C(Cl)Cl>[CH3:28][N:2]([CH3:1])[C:3](=[O:27])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:16][N:17]([C:30]3[C:31]4[C:38]([CH3:39])=[CH:37][NH:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3ccccc3)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(Cc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 120 °C
Yield: 81 %

Procedure:
3-(4-benzylpiperidine-4-carboxamido)phenyl dimethylcarbamate (0.140 g, 0.336 mmol) from step B, 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.056 g, 0.336 mmol), N,N-diisopropylethylamine (0.175 mL, 1.00 mmol), and isopropanol (5 mL) were combined and heated at 120° C. overnight in a pressure vessel. The reaction was diluted with CH2Cl2, washed with H2O and brine, dried over MgSO4, and concentrated under vacuum. The residue was taken up in hot ethanol/H2O. Upon cooling, the product precipitated out of solution to give the title compound in 81% yield.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][N:28]3[CH2:29][CH2:30][CH:25]([C:21]4[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=4)[CH2:26][CH2:27]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-n4ccnc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(1H-imidazol-1-yl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 403.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:12]([Cu])#[N:13]>CN1C(=O)CCC1>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc2cnccc2c1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2cnccc2c1
Temperature: 170 °C

Procedure:
6-Bromoisoquinoline (0.876 g, 4.18 mmol) purchased from Gateway Chemical Technology, Inc. was mixed with CuCN (1.12 g, 12.54 mmol) in 5 mL NMP in a microwave heating tube. The tube was heated under microwave to 150° C. for 1 hour and 170° C. for one hour. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. After removing the solvent, the remaining residue was passed through a silica gel plug using 5% 2M ammonia in MeOH in DCM as the eluant. The crude product (100 mg) was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][O:13][C:12]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:11]3[CH2:10]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:23]=[C:24]([N:38]2[CH2:42][CH:41]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[O:40][C:39]2=[O:48])[CH:25]=[C:26]([F:37])[C:27]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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:21][C:22]1[CH:23]=[C:24]([N:38]2[CH2:42][CH:41]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[O:40][C:39]2=[O:48])[CH:25]=[C:26]([F:37])[C:27]=1[C:2]1[CH:7]=[N:6][C:5]([O:8][CH:9]2[CH2:14][O:13][C:12]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:11]3[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(=O)NCC1CN(c2cc(F)c(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Reactant: O=[N+]([O-])c1cn2c(n1)OCC(Oc1ccc(Br)cn1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCC1CN(c2cc(F)c(-c3ccc(OC4COc5nc([N+](=O)[O-])cn5C4)nc3)c(F)c2)C(=O)O1
Temperature: 80 °C
Yield: 42.8 %

Procedure:
To a suspension of 6-(5-bromo-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (200 mg, 0.515 mmol), N-{3-[3,5-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (238 mg, 0.60 mmol) (Biswajit et. al. WO 2006038100 A1 and Gravestock et. al. WO2004/078753 A1), Pd(Ph3P)4(70 mg) and K2CO3 (150 mg) in DMF/H2O (10/1.5.5 mL) was degassed. The mixture was heated to 80° C. for 2 h, diluted with EtOAc, washed with brine and concentrated in vacuo to give a crude product. The crude product was purified by flash chromatography (5% MeOH in EtOAc) to afford the title product (117 mg, 43%). ESI MS m/z 531.5 (M+H+). 1H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 8.28 (t, J=6.0 Hz, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.46 (d, J=10.4 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 5.77 (s, 1H), 4.80-4.68 (m, 3H), 4.48-4.40 (m, 2H), 4.14 (t, J=9.4 Hz, 1H), 3.75 (dd, J=9.2, 6.4 Hz, 1H), 3.41 (t, J=5.4 Hz, 2H), 1.82 (s, 3H).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(OC(C)(C)C)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:32]1([C:35]2[C:36]([O:49][CH2:50][C:51]34[C:57]([F:59])([F:58])[CH:56]3[CH2:55][CH2:54][CH2:53][CH2:52]4)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=2)[C:40]([O:42]C(C)(C)C)=[O:41])[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[C:36]([O:49][CH2:50][C:51]34[C:57]([F:59])([F:58])[CH:56]3[CH2:55][CH2:54][CH2:53][CH2:52]4)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=2)[C:40]([OH:42])=[O:41])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Product: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 6 and making non-critical variations to replace tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]-heptan-1-yl)methoxy)-2-fluorobenzoate, the title compound was obtained (0.48 g, 80%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.4 Hz, 1H), 6.51 (d, J=12.6 Hz, 1H), 4.00-3.90 (m, 2H), 1.97-1.71 (m, 5H), 1.47-1.22 (m, 5H), 0.95-0.86 (m, 2H), 0.69-0.61 (m, 2H).