Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH:6]=[C:5]2[O:15][C@H:16]1[CH2:20][N:19](C(OC(C)(C)C)=O)[C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]1.[CH:32]([B-](F)(F)F)=[CH2:33].[K+].CCN(CC)CC>CCO.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].C(Cl)Cl>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([O:15][C@H:16]3[CH2:20][NH:19][C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]3)=[CH:6][C:7](=[O:14])[NH:8]2)=[CH:3][C:2]=1[CH:32]=[CH2:33]
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(=O)[nH]c3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc2c(O[C@H]3CN[C@H](C(=O)OC)C3)cc(=O)[nH]c2cc1OC
Temperature: 25 °C
Yield: 127.9 %

Procedure:
To a solution of the product from Step 2 (2.26 g, 4.54 mmol) in EtOH (45.4 mL) was added potassium vinyltrifluoroborate (0.913 g, 6.82 mmol), Et3N (0.950 mL, 6.82 mmol), and PdCl2(dppf)-DCM adduct (0.186 g, 0.227 mmol). The reaction mixture was then heated to reflux for 1 hour, cooled to RT; the volatiles were evaporated in vacuo; and the residue partitioned between EtOAc and water. The organic phase was dried over MgSO4, and the solvent was removed in vacuo. The crude material was purified on silica (gradient elution, 0-5% MeOH/DCM) to yield 2.0 g of the title compound. LRMS ESI+ ((M-Boc)+H)+ 345.3.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:47]=[C:46]([S:48]([N:51](CC2C=CC(OC)=CC=2OC)[C:52]2[S:53][CH:54]=[N:55][N:56]=2)(=[O:50])=[O:49])[C:45]([F:68])=[CH:44][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])=[CH:14][C:13]=1[C:28]1[N:32]([CH:33]2[CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]2)[N:31]=[CH:30][CH:29]=1>ClCCl>[NH:35]1[CH2:34][CH:33]([N:32]2[C:28]([C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:26])([F:27])[F:25])[CH:16]=[CH:17][C:12]=3[O:11][C:10]3[C:9]([Cl:8])=[CH:47][C:46]([S:48]([NH:51][C:52]4[S:53][CH:54]=[N:55][N:56]=4)(=[O:50])=[O:49])=[C:45]([F:68])[CH:44]=3)=[CH:29][CH:30]=[N:31]2)[CH2:36]1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4C(F)(F)F)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccccc3C(F)(F)F)cc2-c2ccnn2C2CNC2)cc1F
Temperature: 40 °C
Yield: 143.6 %

Procedure:
Trifluoroacetic acid (0.55 mL, 7.18 mmol) was added to a solution of tert-butyl 3-{5-[4-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,3,4-thiadiazol-2-yl)amino]sulfonyl}-5-fluorophenoxy)-2′-(trifluoromethyl)biphenyl-3-yl]-1H-pyrazol-1-yl}azetidine-1-carboxylate (Preparation 45, 228 mg, 0.253 mmol) in dichloromethane (20 mL). The mixture was then heated to 40° C. for 18 hours under an atmosphere of nitrogen. The reaction was then cooled to room temperature and concentrated in vacuo to afford a clear oil (236.5 mg). The oil was then purified by preparative HPLC (Trilution method) to afford the title compound as a white solid (42.9 mg, 9% over 2 steps).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[C:6]([OH:19])[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([O:19][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)[CH2:29][CH:28]=[CH2:27]
Reactant: C=CCCBr
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCOc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Yield: 41.4 %

Procedure:
Next, 10.4 g of the 4,4'-dinitro-2-hydroxybiphenyl thus obtained was dissolved in 95 mL dry acetone. 5.52 g of potassium carbonate and 7.56 g of 4-bromo-1-butene were added, and the resulting mixture was heated under reflux for 71 hours. Workup by the usual methods gave 5.20 g of 2-(3-butenyloxy)-4,4'-dinitrobiphenyl as a light yellow powder.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:24]([NH:23][CH2:20][CH2:21][CH3:22])=[O:25])#[N:3]
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CCCN=C=O
Agent: [Cl-]
Product: CCCNC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 176c) and propyl isocyanate in 100% yield as a light yellow solid. MS 333 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([F:18])=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OC(C)=O
Temperature: 83 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (2.17 g), 4-fluoroaniline (1.00 mL) and isopropanol (40 mL) was stirred at 83° C. overnight. The reaction mixture was cooled to room temperature and filtered, the residue was washed with 100 mL of isopropanol and dried to afford the desired compound as a solid (2.42 g, 85.90%)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:21][C:22]1([F:41])[CH2:27][CH2:26][CH:25]([NH:28][C:29](=O)[O:30]C2C=CC([N+]([O-])=O)=CC=2)[CH2:24][CH2:23]1.CO>CC#N>[F:21][C:22]1([F:41])[CH2:23][CH2:24][CH:25]([NH:28][C:29]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:30])[CH2:26][CH2:27]1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(NC1CCC(F)(F)CC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CO
Product: O=C(NC1CCC(F)(F)CC1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (80 mg, 0.29 mmol) in MeCN (2 mL) was added 4-nitrophenyl 4,4-difluoro-cyclohexylcarbamate (217 mg, 0.72 mmol). The resulting mixture was then subjected to microwave irradiation at 120° C. for 15 min. Then, MeOH (0.5 mL) was added and the mixture was filtered. The filtrate was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound, which was dissolved in MeOH (1 mL). The solution was then passed through PL-HCO3 and the resin was washed with MeOH (2×0.3 mL). The combined filtrates were concentrated and dried in vacuo to give the title compound as a light-yellow solid. MS (ESI, positive ion) m/z: 439 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][C:34]([C@@H:36]1[CH2:41][NH:40][CH2:39][CH2:38][NH:37]1)=[O:35]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:39][CH2:38][NH:37][C@H:36]([C:34]([NH:33][CH3:32])=[O:35])[CH2:41]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CNC(=O)[C@@H]1CNCCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CNC(=O)[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
(2S)-4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2S)-piperazine-2-carboxylic acid methylamide following General Procedure C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[N:13][OH:14])[CH:10]([CH3:12])[CH3:11].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:14][N:13]=[C:9]([C:3]1[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH:10]([CH3:12])[CH3:11])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(=NO)c1c(O)cccc1O
Product: CC(=O)ON=C(c1c(O)cccc1O)C(C)C
Yield: 32.7 %

Procedure:
1-(2,6-dihydroxyphenyl)-2-methyl-1-propanone oxime (Intermediate 38, 320 mg) was stirred in acetic anhydride (0.928 ml, 9.84 mmol) at room temperature for 1 hour. After removal of the volatiles, the crude was washed with water, filtered and dried. The residue obtained was charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/ethyl acetate (from 100/0 to 0/100) to afford the title compound (127 mg).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11]1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33].CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11]1)[C:3]1[N:4]=[CH:5][C:6]([NH:9][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])=[CH:7][CH:8]=1
Reactant: CN(c1ccc(N)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(N(C)[C@@H]2CCN(c3ncnc4c3ccn4COCC[Si](C)(C)C)C2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
To a solution of (R)—N2-methyl-N-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-pyridine-2,5-diamine (0.25 mmol) in DCM (5 mL) were subsequently added ethanesulfonyl chloride (0.3 mmol) and Et3N (0.3 mmol). The solution was stirred at the ambient temperature for 18 hours and then concentrated. The crude product was purified by preparative TLC to give the title compound in 42% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:28]=O)=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:28]=[C:10]3[C:3]4[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=4[NH:8][C:9]3=[O:11])=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1Nc2ncnc(Cl)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Yield: 92.5 %

Procedure:
4-Chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1 eq.) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (1 eq.) and triethylamine in ethanol at room temperature to give (92.5%) of 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (2-morpholin4-yl-ethyl)-amide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[S:12](N)(N)(=[O:14])=[O:13]>COCCOCCOC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][S:12](=[O:14])(=[O:13])[O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: NS(N)(=O)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1ccc2c(c1)OS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diethylene glycol dimethyl ether (350 ml) solution of 2-Amino-5-Nitrophenol (40 g) and sulfamide (25 g) was added dropwise to refluxing diethylene glycol dimethyl ether (100 ml) over a period of 50 minutes. Mixture was stirred and refluxing continued 15 minutes, then cooled to room temperature. Solvent was evaporated off, and 500 ml of 1N hydrochloric acid was added. Reaction mixture was extracted with diethyl ether, extract was dried over magnesium sulfate and solvent was removed in vacuo. Crude product was purified by the column chromatography on silica gel (2% Methanol-Ethyl acetate) to give the desired intermediate, 10.5 g.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.[C:13]([Cl:19])(=O)[CH2:14][C:15]([Cl:17])=O>O1CCCC1.[OH-].[Na+]>[Cl:17][C:15]1[CH:14]=[C:13]([Cl:19])[N:3]2[N:4]=[CH:5][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]2[N:1]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Nc1n[nH]cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1cc(Cl)n2ncc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
There was dissolved, in tetrahydrofuran (4 mL), 3-amino-4-phenyl-pyrazole (208 mg, 1.31 mM), then malonyl chloride (153 μL, 1.57 mM) was added to the solution with ice-cooling and the mixture was stirred at room temperature for 30 minutes. To the reaction solution, there was added malonyl chloride (15 μL, 0.16 mM) and the mixture was further stirred at room temperature for 30 minutes. This reaction liquid was diluted with a 1M aqueous sodium hydroxide solution, washed with ethyl acetate, the aqueous phase was acidified (pH 2) by the addition of hydrochloric acid and then it was extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was then distilled off and the resulting solid was washed with diethyl ether. Phosphoryl chloride (4 mL) was added to the resulting solid with ice-cooling, and then the resulting suspension was stirred for 6 hours while refluxing the same with heating. The phosphoryl chloride was distilled off from the reaction liquid, ethanol was added to the resulting residue with ice-cooling and the mixture was stirred for 15 minutes. After the reaction liquid was concentrated, the concentrate was diluted with water and then extracted with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:10) to thus give the title compound (47.7 mg, overall yield of these two steps: 14%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:7]=1[C:13]([F:16])([F:15])[F:14])(=[O:5])=[O:4].C([O-])(=O)C.[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39](I)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.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].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:17])[CH3:1])(=[O:5])=[O:4])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:8]=4)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N(C)C)c(C(F)(F)F)c4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 62.8 %

Procedure:
A mixture of 0.480 g of N,N-dimethyl-4-bromo-2-trifluormethylbenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1″-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 120° under N2 for 7 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30-25:1). Concentration of the chromatographically pure fractions and crystallisation (twice) from ethylacetate gives 0.31 g of the title compound as a solid of m.p. 189-190° C. The mass spectrum shows the molecular peak MH+ at 506.2 Da.
Reaction SMILES: N1C=CC=C(CN)C=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH2:14].[F:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][N:25]2[C@@H:29]([CH3:30])[CH2:28][N:27]([C:31]3[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=3)[C:26]2=[O:40])=[CH:22][CH:21]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH:14][C:37]([C:33]1[S:32][C:31]([N:27]2[CH2:28][C@@H:29]([CH3:30])[N:25]([CH2:24][C:23]3[CH:41]=[CH:42][C:20]([F:19])=[CH:21][CH:22]=3)[C:26]2=[O:40])=[N:35][C:34]=1[CH3:36])=[O:38]
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(F)c(F)c1
Agent: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(F)c(F)c1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with 3,4-difluorobenzylamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid the title compound was obtained as a white solid: mp 134-135° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.54 (t, J=5.9 Hz, 1H), 7.44-7.30 (m, 4H), 7.21-7.12 (m, 3H), 4.60 (d, J=15.6 Hz, 1H), 4.35 (d, J=5.9 Hz, 2H), 4.30 (d, J=15.6 Hz, 1H), 4.19 (dd, J=10.0, 9.1 Hz, 1H), 3.80-3.69 (m, 1H), 3.55 (dd, J=10.0, 6.8 Hz, 1H), 2.47 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 475.0 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:18][C:15]([F:16])([F:17])[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 4-(2,2,2-trifluoro-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (15.15 g, 53.69 mmol) in CH2Cl2 (60 mL) was added trifluoroacetic acid (18 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation. Diethyl ether (100 mL) was added to the residue. The white solid was collected by filtration, washed with diethyl ether, and dried under vacuum. The resulting residue, the title compound, was used in the next reaction without further purification. MS m/z (M+H+) 183.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]3[N:13]([N:15]=[CH:16][C:17]=3[C:18]([NH2:20])=O)[CH:14]=2)=[CH:5][CH:4]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][C:12]3[N:13]([N:15]=[CH:16][C:17]=3[C:18]#[N:20])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cnc3c(C(N)=O)cnn3c2)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc3c(C#N)cnn3c2)cc1

Procedure:
A solution of 6-(4-methoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid amide (1-3, 150 mg, 0.56 mmol, 1 equiv) in dioxane (50 mL) was heated to reflux. After the solid was solvated, Burgess reagent (134 mg, 0.56 mmol, 1.0 equiv) was added. More Burgess reagent (4 equivalents) was added in three equal portions over 3 hours after which TLC indicated the starting amide had been consumed. The solvent was removed in vacuo and the yellow residue was partitioned between EtOAc (2×200 mL) and water (330 mL). The combined organic layers were dried over sodium sulfate and concentrated. The yellow residue was then suspended in ether and filtered to afford 6-(4-methoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile (1-4).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1>C1COCC1>[O:25]=[C:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:7])=[CH:27][CH:26]=3)=[O:15])=[CH:17][CH:18]=2)[NH:22]1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Reactant: O=C(Cl)c1cccs1
Solvent: C1CCOC1
Product: O=C1Cc2ccc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
A dry 25 mL flask was charged with Thiophene-2-carbonyl chloride (0.756 g, 5.16 mmol) and THF (10 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.02 g, 3.98 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure Thiophene-2-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.924 g, 2.53 mmol, 64%).
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][O:6][C:7]1[C:12]2=[CH:13][CH:14]=[C:15]3[C:24]([N:23]=[C:22]4[C:17]([CH:18]=[CH:19][CH:20]=[C:21]4[C:25]([OH:27])=[O:26])=[N:16]3)=[C:11]2[CH:10]=[CH:9][CH:8]=1>CO>[CH3:1][O:26][C:25]([C:21]1[C:22]2[C:17](=[N:16][C:15]3[C:24]([N:23]=2)=[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[C:12]2=[CH:13][CH:14]=3)[CH:18]=[CH:19][CH:20]=1)=[O:27]
Reactant: CC(=O)Cl
Reactant: COc1cccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Solvent: CO
Product: COC(=O)c1cccc2nc3ccc4c(OC)cccc4c3nc12

Procedure:
Acetyl chloride (4.6 mL) was added dropwise to a suspension of 4-methoxy-benzo[a]phenazine-11-carboxylic acid (II.1, see Reference Example 1A, 4.9 g) in methanol (50 mL). The mixture was heated to reflux for 4 hours. The volatiles were then removed in vacuo to yield the title compound as a dark solid (quantitative yield).