Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:3][CH2:4][CH3:5])#[CH:2].[B]1OC2C(=CC=CC=2)O1.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21](Cl)=[N:20][C:19]=1[NH2:25].[OH-].[Na+]>O1CCCC1.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.O1CCOCC1>[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([CH:2]=[CH:1][O:3][CH2:4][CH3:5])=[N:20][C:19]=1[NH2:25]
Reactant: C#COCC
Reactant: COC(=O)c1ccc(Cl)nc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [B]1Oc2ccccc2O1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC=Cc1ccc(C(=O)OC)c(N)n1
Reaction time: 1.5 h
Yield: 68.3 %

Procedure:
To a solution of ethyl ethynyl ether (3.6 g, 25.7 mmol) in tetrahydrofuran (10 mL) was added catechol borane (3.08 g, 25.7 mmol) on an ice bath. Immediately, the cold bath was removed, the reaction mixture was allowed to room temperature, and then, the solution was stirred for 1.5 hours under reflux. This reaction mixture was allowed to room temperature. To this mixture solution were added 2-amino-6-chloro-nicotinic acid methyl ester (1.6 g, 8.57 mmol), sodium hydroxide powder (1.13 g, 28.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.99 g, 0.857 mmol) and dioxane (20 mL), which was then stirred for 2 hours under reflux. The reaction mixture was allowed to room temperature, and partitioned into water and ethyl acetate. The organic layer was separated, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography, and the title compound (1.30 g, 5.85 mmol, 68%) was obtained as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38](Cl)[C:33]=2[CH:32]=[CH:31]1)=[O:29].[NH2:40][C:41]1[CH:42]=[C:43]([S:47]([NH2:50])(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([S:47](=[O:49])(=[O:48])[NH2:50])[CH:42]=3)[C:33]=2[CH:32]=[CH:31]1)=[O:29]
Reactant: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Cl)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Nc6cccc(S(N)(=O)=O)c6)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide, (50 mg, 0.09 mmol), prepared as in reference 3, in glacial acetic acid (2 mL) is mixed with 3-aminobenzenesulfonamide (31 mg, 0.18 mmol) and shaken at 80° C. for 24 hours. The resulting mixture is directly purified by preparative HPLC-MS to give 4-(3-sulfamoyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide (35.3 mg, yield 57%); 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 10.64 (s, 1H), 10.10 (s, 1H), 9.58 (s, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 8.17 (d, J=8.1 Hz, 1H), 8.14 (s, 1H), 7.87 (d, J=3.9 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.53 (d, 5.9 Hz, 1H), 7.37 (s, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.11 (d, J=3.9 Hz, 1H), 2.44 (s, 3H), 2.33 (s, 3H); ESIMS m/z 690.1 (M++1).
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)(=O)C>[C:13]([O:3][C:2]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]=[CH2:9])=[CH:10][C:1]=1[O:11][CH3:12])(=[O:15])[CH3:14]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=CCc1ccc(OC(C)=O)c(OC)c1
Temperature: 140 °C
Yield: 100 %

Procedure:
Into a three-neck, 5000 ml round bottom flask equipped with an addition funnel, mechanical stirrer, condenser, thermometer, heating mantle and nitrogen inserting tube is charged eugenol (2,519 grams, 15.3 moles). The eugenol was heated to 75° C. The acetic anhydride (1554 grams, 15.2 moles) was added with stirring over a one-hour period. The reaction mixture was then heated to 140° C. and stirred for 3 hours. The acetic acid by-product from the acylation reaction was stripped from the reaction mixture at 36° C. and 0.15 mm Hg pressure. The reaction produced 3-(4-acetoxy-3-methoxyphenyl)propene (3134 grams, 99.3 percent yield.)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[CH:13][C:14]=1[NH2:15])=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(N)ccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc2ncccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
To a solution of 540 mg (2.19 mmol) of the above 6-amino-quinoline-5-carboxylic acid methyl ester in 10.8 mL of dioxane and 0.54 mL of methanol is added 5.48 mL (5.48 mmol) of an aqueous solution of NaOH 1N. The reaction is stirred 24 hours at ambient temperature. Then the solvents are evaporated in vacuo and the residue is suspended in a minimum of water and precipitated at pH 6 by addition of concentrated HCl. After filtration and washing with a minimum of water the solid obtained is dried on high vacuum pump to give 245 mg (60%) of a yellowish solid; LC/MS:189/190 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.[Cl-].COC1N=C([N+]2(C)CCOCC2)N=C(OC)N=1.Cl.[CH3:36][S:37]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([C:49]1[CH:54]=[C:53]([O:55][CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[N:52]=[CH:51][N:50]=1)[CH2:44][CH2:43]2)(=[O:39])=[O:38]>O.C(O)C>[CH3:36][S:37]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([C:49]1[N:50]=[CH:51][N:52]=[C:53]([O:55][CH:56]3[CH2:61][CH2:60][N:59]([C:4](=[O:6])[CH2:3][CH:2]([OH:1])[CH3:7])[CH2:58][CH2:57]3)[CH:54]=1)[CH2:44][CH2:43]2)(=[O:39])=[O:38]
Reactant: CC(O)CC(=O)O
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.3 %

Procedure:
3-hydroxybutanoic acid (61 μL, 0.66 mmol), diisopropylethylamine (102 μL, 0.571 mmol), and 4-(dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (235 mg, 0.849 mmol) were added to an ethanol (3 mL) suspension of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline hydrochloride (224 mg, 0.545 mmol) produced in Reference Example 27, and the mixture was stirred at room temperature for 3 days. To the reaction solution, water was added, followed by extraction with dichloromethane three times. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by thin-layer silica gel chromatography (dichloromethane:methanol=1:1, V/V). The obtained crude product was washed with diisopropyl ether to obtain the title compound as grayish white foam (174 mg, yield: 69%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]=2[N:7]([CH3:16])[C:6]1=[O:17].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH2:35]1[CH2:40][O:39][CH:38]=[CH:37][CH2:36]1.O>C(Cl)Cl>[CH3:16][N:7]1[C:8]2[S:14][CH:13]=[C:12]([CH3:15])[C:9]=2[C:10](=[O:11])[N:5]([CH2:4][CH2:3][CH2:2][O:1][CH:38]2[CH2:37][CH2:36][CH2:35][CH2:40][O:39]2)[C:6]1=[O:17]
Reactant: Cc1csc2c1c(=O)n(CCCO)c(=O)n2C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: Cc1csc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
To a solution of 3-(3-hydroxypropyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9 g, 35.4 mmol) and PPTS (900 mg, 3.54 mmol) in DCM (90 mL) at 0° C. was added DHP (8.96 g, 0.106 mol) dropwise. The reaction was stirred at RT for 18 h, poured into water (30 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography and eluted with PE/EA (4:1) to give 1,5-dimethyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (11.2 g, 93.4% yield) as a yellow oil. LCMS: [MH+-THP] 255 and TR=1.473 min.
Reaction SMILES: CN(C)CCC[N:6]1[CH2:11][CH2:10][N:9]([N:12]2[NH:16][CH:15]=[C:14]([C:17]3[N:18]([CH3:25])[C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=3)[S:13]2)[CH2:8][CH2:7]1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1N1CCNCC1.CN(C)CCCN1CCNCC1>>[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[N:6]1[CH2:11][CH2:10][N:9]([N:12]2[NH:16][CH:15]=[C:14]([C:17]3[N:18]([CH3:25])[C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=3)[S:13]2)[CH2:8][CH2:7]1
Reactant: CN(C)CCCN1CCN(N2NC=C(c3ncc([N+](=O)[O-])n3C)S2)CC1
Reactant: c1csc(N2CCNCC2)n1
Agent: CN(C)CCCN1CCNCC1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCN(c3nccs3)CC2)S1

Procedure:
The preparation of the subject compound is carried out essentially as described for the 2-[4-(3-dimethylaminopropyl)-1-piperazinyl] derivative (Example 35), an equivalent of 1-(2-thiazolyl)piperazine replacing the 1-(3-dimethylaminopropyl)piperazine. After recrystallization from 2-methoxyethanol, the pure compound melts at 297°-300° C.
Reaction SMILES: C([S:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][CH:12]=[C:13]([C:15]#[N:16])[N:14]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:38]2[C@H:39]([CH3:62])[C@H:40]3[C@@H:57]([C@H:58]([OH:60])[CH3:59])[C:56](=[O:61])[N:41]3[C:42]=2[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:15]([C:13]1[N:14]=[C:10]([N:7]2[CH2:8][CH2:9][C@H:5]([S:4][C:38]3[C@H:39]([CH3:62])[C@@H:40]4[C@@H:57]([C@H:58]([OH:60])[CH3:59])[C:56](=[O:61])[N:41]4[C:42]=3[C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:6]2)[S:11][CH:12]=1)#[N:16]
Reactant: CC(=O)S[C@H]1CCN(c2nc(C#N)cs2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3CCN(c4nc(C#N)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of (3S)-3-acetylthio-1-(4-cyano-1,3-thiazol-2-yl)pyrrolidine (137 mg, 0.541 mmol) (obtained as described in Reference Example 19) in dimethylformamide (7 ml) was added hydrazine acetate (60 mg, 0.649 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (322 mg, 0.541 mmol) in acetonitrile (16 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.376 ml, 2.16 mmol). The mixture was stirred for 2 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1:3) and ethyl acetate as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[(3S)-1-(4-cyano-1,3-thiazol-2-yl)pyrrolidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (251 mg, yield 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O.CCCCCC>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:25])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(F)cc(Cl)c2c1OCCC2
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OCCC3)c1=O
Yield: 92.4 %

Procedure:
By a method analogous to that of Example 1, Step G, 2.9 grams (0.008 mole) of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)-6-trifluoromethyluracil was reacted with 2.2 grams (0.016 mole) of potassium carbonate and 1.7 grams (0.012 mole) of methyl iodide in 50 mL of N,N-dimethylformamide. The crude reaction product was subjected to column chromatography on silica gel, with 1:9 to 1:4 ethyl acetate:hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.8 grams of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)-1-methyl-6-trifluoromethyluracil, mp 141°-145° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH2:31])=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.[CH:32](=O)[CH3:33].[BH3-]C#N.[Na+]>CO.CC(O)=O.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH:31][CH2:32][CH3:33])=[N:6][C:7]([CH:18]3[CH2:19][CH2:20]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:2][CH2:3]1
Reactant: CC=O
Reactant: N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To a solution of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine (0.15 g, 0.33 mmol) in MeOH (3.3 mL) was sequentially added acetaldehyde (22 mg, 0.5 mmol) and AcOH (5 drops). This mixture was stirred for 30 min before addition of NaBH3CN (1 M solution in THF, 0.6 mL, 0.6 mmol). Stir at rt overnight. Add additional acetic acid (2 drops), acetaldehyde (29 μL, 0.5 mmol) and NaBH3CN (1 M solution in THF, 0.6 mL, 0.6 mmol). After 2 hr, add additional acetic acid (2 drops), acetaldehyde (29 μL, 0.5 mmol) and NaBH3CN (1 M solution in THF, 0.6 mL, 0.6 mmol). After 3 hr, dilute mixture with EtOAc and wash with sat. aq. NaHCO3 and extract with EtOAc (3×40 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 100% ethyl acetate) to afford 0.16 g (44%) of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N2-ethyl-2,3-dihydro-1H-indene-1,2-diamine as a solid: 1H NMR (CDCl3) δ 0.84–1.05, 1.62–1.75, 2.78–2.86, 3.31–3.37, 3.52, 5.22, 5.52, 7.28–7.51; MS (ESI+) for C27H28Cl2N4 m/z 479 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=1>CCOC(C)=O>[OH:44][CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:38][CH:39]=1
Reactant: Nc1ccc(CO)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CO)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 300 mg, 0.746 mmol) and THF (7.5 mL). To the resulting solution was added (4-amino-phenyl)-methanol (133 mg, 0.955 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and the resulting suspension was filtered. The solids collected were washed with 0° C. iPrOH (5 mL) and set aside. The filtrate was concentrated in vacuo and the residue obtained was dissolved in EtOAc (5 mL). The resulting solution was triturated with Hexanes (˜50 mL) to yield a precipitate. This precipitate was then filtered and washed with 0° C. iPrOH (5 mL). The solids collected were combined with those previously set aside to afford the title compound in 24% yield (0.091 g, 0.179 mmol).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[O-2].[Mg+2].[Cl:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]>C1COCC1.O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[S:14]([C:12]1[S:13][C:9]([Cl:8])=[C:10]([N+:18]([O-:20])=[O:19])[CH:11]=1)(=[O:16])=[O:15]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: CNCCO
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCO)S(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A suspension of 2-(methylamino)-ethanol (0.29 g, 3.86 mmol) and magnesium oxide (0.77 g, 19.1 mmol) in THF (4 ml) and water (1.4 ml) was allowed to stir at room temperature for 30 min, 5-chloro-4-nitrothiophene-2-sulfonyl chloride (1.0 g, 3.81 mmol) dissolved in THF (1.6 ml) was added drop wise at room temperature over a period of 1 h and the reaction mixture was allowed to stir for an additional hour. Filtration over Decalite and evaporation yielded the crude product which was further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (0.4 g, 35%) as a yellow solid. MS (EI) 300.0 [(M)+], mp 62° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH:21]5[CH2:22][CH2:23]5)(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([NH2:30])=[N:32][CH:33]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)C5CC5)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (Example 39) following General Procedure B-3 was reacted with 2-aminopyridine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 123. (400 MHz, CDCl3): 0.91-0.94 (2H, m, CH2), 1.10-1.12 (2H, m, CH2), 2.20 (1H, m, CH), 2.58-2.60 (4H, m, CH2), 3.29-3.31 (4H, m, CH2), 3.79-3.82 (6H, m, CH2), 3.94-3.97 (4H, m, CH2), 4.55 (1H, b, NH2), 6.47 (1H, d (J=0.62), ar), 7.22 (1H, s, ar), 8.38 (1H, dd (J=8.89, 2.27), ar), 9.08 (1H, dd (J=2.20, 0.49), ar). (M+H)+ 516.37
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.Cl>C1COCC1>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCCC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCC(O)c1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
n-Hexyl magnesium bromide (2.0 M in Et2O, 27 mL, 54 mmol) was added to a solution of 4-bromobenzaldehyde (5.0 g, 27 mmol) in THF (20 mL) at 0° C. under nitrogen. After 1.5 h at 0° C., the reaction was 3 N HCl (20 mL) and concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with Et2O (3×150 mL). Combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5%→10% EtOAc/Hex) afforded 5.6 g (76%) of 1-(4-bromophenyl)-heptan-1-ol.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:34])[CH:6]([OH:33])[CH:7]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=2[N:23]2[CH:31]=[C:30]3[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]3)=[N:24]2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.ClCCl>>[CH:1]1([NH:4][C:5](=[O:34])[C:6](=[O:33])[CH:7]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=2[N:23]2[CH:31]=[C:30]3[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]3)=[N:24]2)[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-n1cc2ccccc2n1
Solvent: ClCCl
Product: O=C(NC1CC1)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
To a solution of N-[4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl]-2-(2H-indazol-2-yl)nicotinamide (116 mg, 0.255 mmol) in dichloromethane (30 ml) Dess-Martin periodinane (commercial solution of 15% by weight in dichloromethane; 1 ml, 0.460 mmol) was added and the mixture stirred for 5 minutes. The reaction was then quenched by adding a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3) and water (25 ml each). Afterwards the organic layer was washed twice with water, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The obtained residue was treated with n-pentane (100 ml), filtered off and then refluxed in a mixture of methyl-tert.-butylether (15 ml) and a 4 N solution of HCl in dioxane (50 μl). After stirring for 2 hr at room temperature the solid was filtered off under suction and recrystallized from isopropanol to give 70 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[CH2:16][O:17][CH2:18][O:19][CH3:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:16][O:17][CH2:18][O:19][CH3:20]
Reactant: COCOCc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COCOCc1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.6 %

Procedure:
To a solution of 1-bromo-4-tert-butyldimethylsiloxy-2-methoxymethoxymethylbenzene (34.2 g, 94.8 mmol) in tetrahydrofuran (100 mL) was added tetrabutylammonium fluoride (1 mol/L in tetrahydrofuran, 50 mL), and the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (2:1 hexane/ethyl acetate) to give 4-bromo-3-(methoxymethoxymethyl)phenol (25.9 g, quant).