Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.Cl[C:22]1[C:27]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH2:34])[N:29]=2)=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:1][C:2]1[C:3]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:22]3[C:27]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([NH2:34])[N:29]=4)=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:18][CH:19]=2)=[N:4][N:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=1
Reactant: Nc1nccc(-c2cccnc2Cl)n1
Reactant: Cc1cn(-c2ccccc2)nc1Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cn(-c2ccccc2)nc1Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
A resealable reaction tube was charged with 4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenol (0.12 g, 0.45 mmol), 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (0.09 g, 0.45 mmol), cesium carbonate (0.30 g, 0.91 mmol), and DMSO (2.26 ml, 0.2 M). The reaction vessel was sealed and the mixture stirred at 130° C. for 16 h. The reaction was cooled to RT, diluted with 1 ml DMSO and passed through a PTFE acrodisc filter via syringe. The residue was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA), and the product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(2-(4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a tan solid. MS m/z=436.2 [M+H]+. Calc'd for C25H21N7O: 435.48.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:17][NH:18][C:19]([C:21]1[CH:22]=[C:23]([NH:27][CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([OH:31])=[O:30])[CH:24]=[CH:25][CH:26]=1)=[O:20].C1C=CC2N(O)N=NC=2C=1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[CH3:17][NH:18][C:19]([C:21]1[CH:22]=[C:23]([NH:27][CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([O:31][C@@H:50]2[CH:51]3[CH2:54][CH2:55][N:48]([CH2:53][CH2:52]3)[CH2:49]2)=[O:30])[CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: CNC(=O)c1cccc(NC(C(=O)O)c2ccccc2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
PS-DCC (798 mg, 0.998 mmol, loading: 1.25 mmol/g) was suspended in dry THF (10 ml). 2-(3-(Methylcarbamoyl)phenylamino)-2-phenylacetic acid hydrochloride (I9) (160 mg, 0.50 mmol), HOBT (153 mg, 0.10 mmol), and (R)-quinuclidin-3-ol (190 mg, 1.50 mmol) were added, and the mixture was shaken at room temperature for 16 hours (UPLC-MS: complete conversion). PS-DCC was removed by filtration and washed with THF and EtOAc. The filtrate was evaporated and the resulting residue was dissolved in EtOAc and washed with NaHCO3, water and brine. The organic layer was separated, dried over Na2SO4, filtered and evaporated. The resulting oil (196 mg, quantitative yield, mixture of diastereomers) was used for the next step without any further purification.
Reaction SMILES: O.[OH-].[Na+].[O:4]=[C:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[N:13](S(C2C=CC(C)=CC=2)(=O)=O)[CH:12]=1>C1COCC1.C(OCC)(=O)C>[O:4]=[C:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[CH:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CC3CCCC3=O)c3cc(C#N)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]cc(C=C3CCCC3=O)c2c1
Reaction time: 16 h
Yield: 66.1 %

Procedure:
Water (50 mL) and sodium hydroxide (50 mL, 10 N) were added to a solution of 3-(2-oxo-cyclopentylmethyl)-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (1.0 g, 2.56 mMol) in THF (200 mL), and the mixture was stirred for 16 h. The reaction was diluted with ethyl acetate (300 mL), quenched with 1N HCl (100 mL), and then poured into a mixture of saturated aqueous sodium bicarbonate (200 mL) and brine (100 mL). The aqueous layer was extracted with ethyl acetate (4×250 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a step gradient of 20% ethyl acetate/hexanes-85% ethyl acetate/hexanes to give 3-(2-oxo-cyclopentylidenemethyl)-1H-indole-5-carbonitrile as a yellow solid (400 mg, 67%) after drying under vacuum. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (1H, s), 7.96 (1H, m), 7.63 (2H, m), 7.55 (1H, m), 2.85 (2H, m), 2.35 (2H, m), 2.00 (2H, m); LCMS (4.6×50 mm XTERRA C-18 S5 column, 5 mL/min, 0–100% MeOH/H2O/0.1% TFA, 2 min gradient): Tr=1.50 min, m/e 237 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCCSc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCSc2ccccc2)CC1
Yield: 27.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.00 g) as starting compound and 5-phenylthiopentyl bromide (1.54 g) were reacted and treated in the same manner as in Example 168 to give 0.70 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-phenylthiopentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:10]1=[O:25])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][O:35][C:36](=[O:38])[N:37]=2)=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CC#N>[C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)[C:10]1=[O:25])[C:6](=[O:7])[NH:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:31][CH:32]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(=O)O[C@@H](C(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a stirred mixture of compound 93-3 (175 mg, 0.50 mmol), DMAP (12 mg, 20 mmol %), and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one 1 (177 mg, 2 eq) in MeCN (2.5 ml) at 0° C., EDCI (191 mg, 2 eq) was added. The resulting mixture was stirred at RT for 2 h. The volatile materials were removed on the rotavap. The residue was purified by silica gel chromatography (MeOH/DCM 0 to 10%) to give compound 96-1 (110 mg).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C.O>[OH:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=c1ccoc(CO)c1O
Reactant: CCOC(=O)CCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCOc1c(CO)occc1=O
Yield: 54 %

Procedure:
To a solution of 2.75 g (0.042 mole) of potassium hydroxide in 38 ml of ethanol and 10 ml of water was added 5.93 g (0.042 mole) of 2-hydroxymethyl-3-hydroxy-4-pyrone, and the resulting mixture heated to 50°. A 12.4 g (0.046 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atomsphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 6.34 g (54%) of oily product, 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-4-pyrone: NMR (CDCl3): δ1.22 (3H, t, J = 7Hz), 2.30 (2H, t, J = 5.5 Hz), 4.63 (2H, s), 6.35 (1H, d, J = 6 Hz), 7.73 (1H, d, J = 6 Hz).
Reaction SMILES: [CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24][C:25]([CH3:31])([CH3:30])[O:26][C:27](=[O:29])[CH:28]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C3(C#N)CC3)=C(F)C=2)CCCC1>>[CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24][C:25]([CH3:30])([CH3:31])[O:26][C:27](=[O:29])[CH:28]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:19]#[N:20])[CH2:16][CH2:17][CH2:18]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Product: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1

Procedure:
The desired product was prepared analogously to Example A(86) step 6, substituting 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile (1.200 g, 2.7 mmol) from step 2 above in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. Yield: 1.00 g, 84%.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)=[C:8]([N+:33]([O-:35])=[O:34])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([N+:33]([O-:35])=[O:34])=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3[N+](=O)[O-])c2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])c2)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a solution of potassium thiocyanate (18.6 g, 192 mmol) in acetic acid (1.0 L) was added N-[3-(4-amino-2-nitrophenoxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide (20 g, 48 mmol), and the mixture was stirred at 50° C. for 10 min. The obtained solution was cooled to room temperature, a solution of bromine (8.05 g, 50.4 mmol) in acetic acid (200 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 16 hr. Then, a solution of potassium thiocyanate (9.3 g, 96 mmol) and bromine (4.02 g, 25.2 mmol) in acetic acid (100 mL) was added, and the mixture was further stirred at room temperature for 4 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (600 mL), water (300 mL) was added, and the mixture was neutralized with 8N aqueous sodium hydroxide solution. The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL×2) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (7.8 g, 34%) as a yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24].[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>C(Cl)(Cl)Cl>[NH2:20][C:10]1[C:9]2[N:8]=[C:7]([CH2:21][O:22][CH2:23][CH3:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:30])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=2[N:11]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Reactant: CC(C)N=C=O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)NC(C)C
Reaction time: 0.75 h
Yield: 76.4 %

Procedure:
A solution of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.1 mmol) in chloroform (36 mL) was cooled to 0° C., and a cold solution of isopropyl isocyanate (0.50 mL, 5.4 mmol) in chloroform (4 mL) was added slowly. A precipitate formed, and the reaction was stirred for 45 minutes. The reaction mixture was triturated with ethyl acetate (200 mL), and the precipitate was isolated by filtration and dried for three days in a drying oven to provide 1.86 g of N-{4-[4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-N′-(1-methylethyl)urea as a white solid, mp 211° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:19])=[C:14](B(O)O)[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:19])=[C:14]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c(B(O)O)c1
Reactant: Clc1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(-c2ccncc2)c1
Temperature: 85 °C
Yield: 66.1 %

Procedure:
A mixture of compound 11 (135 mg, 0.5 mmol), 4-chloropyridine hydrochloride (107 mg, 0.713 mmol), tetrakis(triphenylphosphine)palladium (45 mg, 0.04 mmol) and Na2CO3 (160 mg, 1.51 mmol) in dimethoxyethane (2.2 mL) and water (0.7 mL) mixture, is heated to 85° C. for 5 h. The mixture is cooled to rt and partitioned between water and EtOAc. The organic phase is dried using Na2SO4 and concentrated on rotary evaporator to afford 100 mg (59%) of compound 13. 1H NMR (300 MHz, CDCl3) δ 8.68-8.62 (m, 2H), 7.80-7.42 (m, 2H), 7.40-7.35 (m, 1H), 7.36-7.24 (m, 1H), 7.18-7.08 (m, 1H), 5.26-5.18 (br s, 1H), 4.25 (d, J=5.5 Hz, 2H), 1.44 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([OH:11])[C:7]([F:10])([F:9])[F:8].[H-].[Na+].[CH3:19]I>C(COC)OC>[CH3:19][O:11][C:6]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C:7]([F:9])([F:10])[F:8]
Reactant: CI
Reactant: OC(c1nccs1)(c1nccs1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(c1nccs1)(c1nccs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
1,1-Di(2-thiazolyl)-2,2,2-trifluoroethanol (1 g) was added to a stirred suspension of sodium hydride (80%, 225 mg) in dry dimethoxyethane (50 ml) at 0° C. After 15 minutes, methyl iodide (2.1 g) was added dropwise. The mixture was allowed to warm to room temperature and was then left stirring overnight. The mixture was concentrated by evaporation, then poured into saturated aqueous sodium chloride solution and extracted with dichloromethane. The material thus obtained was purified by flash chromatography to give the title compound as a white solid (950 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[OH:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[OH:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20](=[CH:12][C:9]3[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=3[CH3:11])[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2ccc(O)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(O)ccc32)c(C)c1CCC(=O)O
Yield: 40.1 %

Procedure:
3-(2-carboxyethyl)-2,4-dimethyl-5-formylpyrrole (82 mg), 63 mg 6-hydroxy-2-oxindole, and 48 μL piperidine in 2 mL of ethanol were heated at 90° C. for two days. The reaction mixture was cooled, concentrated, and purified by silica gel column chromotography eluting with ethyl acetate-hexane-acetic acid to give 55 mg (40%) of the title compound as an dark brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:21]1[N:26]=[C:25]([CH2:27][O:28][CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])[CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCO>[OH:19][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:4]2[S:3][C:2]([NH:1][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH2:27][O:28][CH2:29][C:30]([OH:32])([CH3:31])[CH3:33])[N:26]=3)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=2)=[CH:11][CH:12]=1)([CH3:17])[CH3:18]
Reactant: CC(C)(O)COCc1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCO
Product: CC(C)(O)COCc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3)cc2C(N)=O)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Amino-5-[4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.1 g, 0.362 mmol), 1-[(6-bromopyridin-2-yl)methoxy]-2-methylpropan-2-ol (Example 217 Step 1) (0.085 g, 0.326 mmol), Pd2dba3 (0.017 g, 0.018 mmol), K2CO3 (0.055 g, 0.398 mmol) and X-Phos (0.043 g, 0.090 mmol) were added to a 5 mL microwave vial. Degassed EtOH (1 mL) was added and the vial evacuated and back-filled with N2 (3×). The resulting mixture was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with methanol, silica gel was added, and the solvent was removed in vacuo. Purification of the residue by flash chromatography (silica, 0-10% MeOH—CHCl3) gave the title compound as a beige solid after triturating in EtOAc.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[S:8][C:9]([C:12]2[CH2:19][S:18][CH:17]3[N:14]([C:15](=[O:28])[CH:16]3[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]=2[C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:10][N:11]=1.C(N(CC)CC)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH:32]([O:31][C:29]([C:13]1[N:14]2[CH:17]([S:18][CH2:19][C:12]=1[C:9]1[S:8][C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])=[N:11][CH:10]=1)[CH:16]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:15]2=[O:28])=[O:30])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)CCl)s3)CSC12
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
Chloroacetyl chloride (12.37 g) is added to a solution of 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (60 g) in tetrahydrofuran (350 cc) cooled to 0° C., and triethylamine (16.3 cc) is then added in 6 minutes. After 1 hour at 0° C., the reaction mixture is diluted with a half-saturated sodium bicarbonate solution (800 cc) and extracted with ethyl acetate (3×200 cc). The combined organic phases are washed with a saturated sodium chloride solution (250 cc) and dried, after which they are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give an orange froth (78 g) which is recrystallised from acetonitrile (300 cc) to give cream crystals (37.4 g) of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-chloroacetamido-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>O1CCOCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 5.0 g (20.4 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 4.57 g (24.5 mmol) piperazine 1-carboxylic acid tert-butyl ester using 10.4 mL (61.3 mmoL) DIPEA in 50 mL dioxane. The reaction mixture is stirred at 80° C. over night. The solvent is removed under reduced pressure. The residue is taken up in water extracted three times with ethylacetate. The combined organic layers are dried over MgSO4 filtered off and the solvent is removed under reduced pressure yielding 7.5 g (94%) of the desired product, which is used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[C:27]#[N:28])=[CH:4][C:5](=[O:19])[N:6]([CH:8]([CH2:12][CH2:13][O:14][C:15]([F:18])([F:17])[F:16])[C:9](O)=[O:10])[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[C:3]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[C:27]#[N:28])=[CH:4][C:5](=[O:19])[N:6]([CH:8]([CH2:12][CH2:13][O:14][C:15]([F:16])([F:17])[F:18])[C:9]([NH:29][C:30]2[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=2)=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)n(C(CCOC(F)(F)F)C(=O)O)cc1Cl
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CCOC(F)(F)F)n2cc(Cl)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
237 mg (purity 84%, 0.46 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoic acid (racemate) and 97 mg (0.50 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 142 mg (purity 81%, 41% of theory)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][C:23]=3[NH2:25])[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=[C:16]([C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([F:15])[CH:12]=3)[C:24]=12
Reactant: CC(C)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Agent: [Pd]
Solvent: CO
Product: CC(C)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Reaction time: 8 h
Yield: 130.5 %

Procedure:
A solution of -(3-(benzyloxy)-5-fluorophenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (15 mg, 0.04 mmol) in MeOH (0.9 mL) was flushed with argon. Pd on activated carbon (10 mL) was carefully added while keeping reaction under an argon atmosphere. Reaction was flushed with H2 gas and left under H2 atmosphere overnight at room temperature. The reaction was filtered through celite and rinsed with MeOH to yield BA22 (15 mg, 100% yield). ESI-MS (M+H)+ m/z calcd 288.1, found 288.1.