Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O1CCOCC1>[NH:12]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: O
Product: NNc1ccc(C(=O)O)cn1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A suspension of 6-chloronicotinic acid (30.0 g, 189 mmol) in 1,4-dioxane (29.0 mL) was treated with hydrazine hydrate (134 mL, 1.51 mol) and heated to 90° C. overnight. The mixture was cooled to ambient temperature and then in ice for 30 min. Precipitate formation was induced by etching the side of the flask and the precipitate was filtered and re-suspended in EtOH (500 mL) with vigorous stirring. The resulting suspension was filtered. The precipitate was dissolved in water (300 mL) and HCl (6N) was added until pH=1. The pH was then adjusted to 5 with NaOH (50%, aq.) and the resulting suspension was stirred for 1 h. The solids were collected by filtration and dried in vacuum to give the title compound (16.65 g, 57.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.70 (d, 1H) 7.86 (dd, J=8.97, 2.15 Hz, 1H) 8.32 (br. s., 1H) 8.52 (d, J=1.77 Hz, 1H). MS m/z [M+H]+ 154.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[C:2]1([CH2:1][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(CNc2ccccc2)cc1

Procedure:
Benzaldehyde(31.84 g, 0.300 mol) and aniline (27.94 g, 0.300 mol) in benzene (100 ml) were heated to remove the water using a Dean-Stark trap. After 5.4 ml of water had been collected, the benzene was stripped off and the residual oil poured into a beaker. On treating with petroleum ether (10-20 ml) the oil crystallized. This mass was suction filtered and washed with some additional petroleum ether. Recrystallization from hexane gave off-white needles.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].C(N([CH2:21][CH3:22])CC)C.[C:23]1(C)[C:24]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:26]=C[CH:28]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][S:29]([C:24]1[CH:25]=[CH:26][C:21]([CH3:22])=[CH:28][CH:23]=1)(=[O:31])=[O:30]
Reactant: CCN(CC)CC
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 16 h

Procedure:
To a solution of 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethanol (12.5 g, 61 mmol) in dichloromethane (200 mL) at −20° C. under N2 atmophere was added triethylamine (26 mL, 184 mmol) and catalytic amount of 4-dimethylamino pyridine (50 mg). This solution was then treated with toluenesulfonyl chloride (14.1 g, 73.8 mmol) and the reaction was allowed to equilibrate to 23° C. over 16 hours. Reaction was washed with water, 5% Na2CO3, saturated NH4Cl, and brine. Solvent was removed in vacuo and crude tosylate 1 (21.3 g) was carried on to the next step without further purification. M+1=358.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([OH:15])=[O:14].[CH2:22](O)[CH3:23]>Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([O:15][CH2:22][CH3:23])=[O:14]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4-nitrobenzoic acid (1.2 g) in 20% hydrogen chloride in ethanol (3 ml) was refluxed for 2 hours. The mixture was concentrated. The residue was dissolved in ethyl acetate and washed with an aqueous solution of sodium bicarbonate and water successively. The extract was evaporated and the residual oil was crystallized from a mixture of hexane and ethanol to give crystals of ethyl 3-(2,4-difluorophenylthio)-4-nitrobenzoate (1.1 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:35][C:36](=[O:38])[CH3:37])[CH2:7][NH:8][C:9](=[O:34])[C:10]1[C:15]([I:16])=[C:14]([C:17](=[O:30])[NH:18][CH2:19][CH:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[C:13]([I:31])=[C:12]([NH2:32])[C:11]=1[I:33])(=[O:3])[CH3:2].[C:39](Cl)(Cl)=[O:40].C1(C)C=CC=CC=1>O1CCOCC1>[C:23]([O:22][CH2:21][CH:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][NH:18][C:17](=[O:30])[C:14]1[C:13]([I:31])=[C:12]([N:32]=[C:39]=[O:40])[C:11]([I:33])=[C:10]([C:9](=[O:34])[NH:8][CH2:7][CH:6]([O:35][C:36](=[O:38])[CH3:37])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:15]=1[I:16])(=[O:25])[CH3:24]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(=O)OCC(CNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Temperature: 60 °C

Procedure:
To a solution of acetic acid 1-acetoxymethyl-2-[3-amino-5-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-benzoylamino]-ethyl ester (15 g, 17 mmol) in 1,4-dioxane (40 mL) was added a solution of 20% phosgene in toluene (100 mL, 11 eq) at ambient temperature. The mixture was then heated to 60° C. for 15 hours. The reaction mixture was cooled to ambient temperature and then concentrated at reduced pressure to give an off white solid. Dioxane (50 mL×2) was added and removed slowly at reduced pressure to give an off-white solid which was placed on a vacuum line to remove any residual solvent. The material was used without further purification
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][O:36][CH2:37][CH2:38][CH2:39][NH2:40].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:35][O:36][CH2:37][CH2:38][CH2:39][NH:40][C:24]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCCCN
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 72 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (54 mg.) was added, and the admixture was refluxed with heat for 2 minutes. 3-Methoxypropylamine (0.05 ml) was added to the reaction mixture, and the admixture was refluxed with heat for 12 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 51 mg of the title compound (yield: 72%).
Reaction SMILES: [CH3:1][C:2]12[CH2:13][CH2:12][C:9]([CH3:14])([CH2:10][CH2:11]1)[C:8]1[CH:7]=[CH:6][C:5]([OH:15])=[CH:4][C:3]2=1.[Br:16]Br>C(O)(=O)C>[Br:16][C:6]1[C:5]([OH:15])=[CH:4][C:3]2[C:2]3([CH3:1])[CH2:13][CH2:12][C:9]([CH3:14])([C:8]=2[CH:7]=1)[CH2:10][CH2:11]3
Reactant: BrBr
Reactant: CC12CCC(C)(CC1)c1cc(O)ccc12
Solvent: CC(=O)O
Product: CC12CCC(C)(CC1)c1cc(Br)c(O)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1,8-dimethyltricyclo[6.2.2.02,7]dodeca-2(7),3,5-trien-4-ol (Compound 2, 1.58 g, 7.81 mmol) in 10 mL of glacial acetic acid was added bromine (0.40 mL, 7.81 mmol). The reaction mixture was stirred at 25° C. for 4 hours then quenched with 10% Na2S2O3 and extracted with Et2O. The combined ether extracts were washed with water and brine, and dried over Na2SO4, and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:hexane (2:98) to yield the title compound as a yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([NH:34][CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:14][C@@H:13]1[CH2:30][CH2:31][CH2:32][CH3:33])=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:54]>>[ClH:54].[ClH:54].[ClH:54].[NH2:8][CH2:9][CH:10]([NH:34][CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:14][C@@H:13]1[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: ClCCl
Reactant: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1CC(CNC(=O)OC(C)(C)C)NCc1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1CC(CN)NCc1ccc2ccccc2c1
Product: Cl

Procedure:
A solution of 1-(3-tert-butoxycarbonylamino-2-(2-naphthylmethylamino)prop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine (0.313 g, 0.514 mmol) in methylene chloride (10 mL) was deprotected with trifluoroacetic acid (5 mL) and converted to the free base (255 mg) according to the procedure described in Example 1, Step E. Purification of 40 mg by preparative HPLC used gradient elution with solvents A and B (from Example 1; 95% to 5% solvent A). Ion exchange and lyophilization as described furnished the title compound as a white solid. FAB ms (m+1) 509. Anal. Calc. for C33H40N4O.0.05 H2O 4.45 HCl: C, 59.00; H, 6.68; N, 8.34. Found: C, 59.00; H, 6.51; N, 8.44.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:24]=[C:25]([CH:27]=[CH:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[N:26]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16](/[C:19](=[N:22]\[H])/[NH:20][NH2:21])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.O.[C:40]([O-])(O)=O.[Na+]>C(O)=O>[N:21]1[NH:20][C:19]([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:24]=[C:25](/[CH:27]=[CH:28]/[C:29]5[CH:38]=[CH:37][C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:30]=5)[N:26]=[C:8]4[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)=[N:22][CH:40]=1
Reactant: [H]/N=C(/NN)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=Cc4ccc5ccccc5n4)cn23)cn1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: C(=C/c1cn2c(-c3ccc(-c4ncn[nH]4)nc3)cnc(N3CCOCC3)c2n1)\c1ccc2ccccc2n1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of compound 5a (180 mg, 0.370 mmol) in formic acid (3 mL) was stirred in a 10 mL sealed tube at 100° C. for 2 h. After cooling to rt, water (20 mL) was added, and the pH of the solution was adjusted to 7 with saturated NaHCO3 solution. The resulting solids were collected by filtration and washed with Et2O to obtain the title compound 91 as a yellow solid (37 mg, 19% yield). 1H-NMR (300 MHz, DMSO-d6+D2O) δ (ppm): 8.96 (s, 1H), 8.72 (d, J=8.4 Hz, 1H), 8.38-8.32 (m, 4H), 8.19-8.06 (m, 4H), 8.01-7.91 (m, 1H), 7.74-7.68 (m, 2H), 7.58 (s, 1H), 4.45-4.25 (m, 4H), 3.90-3.70 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N9O: 502.2 (M+H). Found 502.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1F)[C:7]([OH:9])=[O:8])([O-])=O.N([O-])=O.[Na+].[N-]=[N+:19]=[N-:20].[Na+].O.[C:23](O)(C(F)(F)F)=O>[Pd]>[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:23])[C:7]([OH:9])=[O:8])=[N+:19]=[N-:20]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C(F)(F)F
Agent: [Pd]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A mixture of 1.04 g (5.62 mmol) 3-nitro-4-fluoro benzoic acid and 105 mg of Pd/C in 10 mL of TFA was stirred for 12 h under an H2 atmosphere. The mixture was then filtered through celite and the filter cake was washed with 20 mL of TFA. The pale yellow solution was then stirred under N2 at 0° C. for 10 min and 405 mg (5.87 mmol) of NaNO2 was added in small portions over 15 min. After an additional 15 min, 400 mg (6.15 mmol) of NaN3 was then added carefully in portions. Gas evolved slowly, and after 1 h the mixture was poured over 20 mL of water and 50 mL of ice. After the ice had melted, the resulting precipitate was filtered and washed with water and hexanes, then dried under vacuum to provide 964 mg of Compound 7 as a white powder.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:19]([N:26]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH2:34]([N+:26]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: c1ccc(CN(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: c1ccc(C[N+](Cc2ccccc2)(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
Tetrabenzyl ammonium para-toluene sulfonate is prepared from benzyl para-toluene sulfonate and tribenzylamine.
Reaction SMILES: [CH:1]([Li])(CC)C.CCCCCC.[CH2:12]([N:15]([CH2:33][CH2:34][CH3:35])[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH2:18][CH2:19][CH2:20][N:21]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13][CH3:14].CI>C1COCC1>[CH3:1][C:23]1[CH:24]=[CH:25][C:16]([N:15]([CH2:12][CH2:13][CH3:14])[CH2:33][CH2:34][CH3:35])=[C:17]2[C:22]=1[N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][CH2:19][CH2:18]2
Reactant: CCCN(CCC)c1cccc2c1CCCN2C(=O)OC(C)(C)C
Reactant: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCCN(CCC)c1ccc(C)c2c1CCCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
s-Butyl lithium (17.7 mL of 1.3 M in hexane (0.045 mol) was added at -78° C. to a stirred solution of t-butyl 1,2,3,4-tetrahydro-5-(dipropylamino)quinoline-1-carboxylate (10 g, 0.030 mol) in THF (200 mL). After 15 minutes, methyl iodide (17.1 g, 0.13 mol) was added and the solution was allowed to warm to room temperature. The THF was removed under reduced pressure, and the residual oil was partitioned between ethyl acetate and water. The ethyl acetate was evaporated and the residual oil was chromatographed on silica gel to afford 10.65 g of t-butyl 1,2,3,4-tetrahydro-8-methyl-5-(dipropylamino)quinoline-1-carboxylate as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C(O[CH:30](OCC)[N:31](C)[CH3:32])C.[CH3:37]O>>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([N:31]([CH3:32])[CH3:30])[N:1]=[CH2:37])[CH:4]=4)[C:18]=23)[CH:25]=[CH:24][CH:23]=1
Reactant: CO
Reactant: CCOC(OCC)N(C)C
Reactant: NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Product: C=NC(c1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1)N(C)C
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A mixture of 500 mg (1.34 mmol) of 3-(3aminomethyl-phenylamino)4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content: 1.79%), 402 mg (2.73 mmol) of N,N-dimethylformamide diethyl acetal and 5 ml of methanol is stirred at 30° C. for 2 hours and then concentrated by evaporation in vacuo. Crystallisation of the residue from ethyl acetate, filtration and washing the filter residue with ethyl acetate yield 4-(3-chloro-phenylamino)-3-[3-(dimethylamino-methyleneamino-methyl)-phenylamino]-1H-pyrazolo[3,4-d]pyrimidine having a water content of 1.68%; m.p. 175-177° C.; ESI-MS: (M+H)+=421.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][C:12]=2[C:20]#[CH:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:46][C@@H:47]([NH2:57])[CH2:48][CH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>CN(C)C=O.C(OCC)(=O)C>[C:20]([C:12]1[CH:13]=[C:14]([C:17]([NH:57][C@H:47]([CH3:46])[CH2:48][CH2:49][CH2:50][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)=[O:18])[CH:15]=[CH:16][C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)#[CH:21]
Reactant: C#Cc1cc(C(=O)O)ccc1-c1ccc(OC)c(OC)c1
Reactant: C[C@@H](N)CCCc1cccnc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#Cc1cc(C(=O)N[C@H](C)CCCc2cccnc2)ccc1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 459 mg of 3',4'-dimethoxy-2-ethynyl[1,1'-biphenyl]-4-carboxylic acid in 8 mL of dimethylformamide was cooled in an ice bath and treated with 0.25 mL of triethylamine and 0.38 mL of diphenylphosphoryl azide. After 1 hour. 0.3 mL of (R)alpha-methyl-3-pyridinebutanamine was added and the reaction mixture was allowed to warm to room temperature over 48 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was chromatographed over 50 g of silica gel eluting with ethyl acetate and the product was crystallized from ethyl acetate-hexane to give 576 mg of (R)-2-Ethynyl-3',4'-dimethoxy-N-[1-methyl-4-(3-pyridinyl)butyl][1.1'-biphenyl]-4-carboxamide, mp 135°-137° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31](=[O:43])[N:32]4[CH2:37][CH2:36][N:35]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:34][CH2:33]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.C(O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][C:31](=[O:43])[N:32]4[CH2:37][CH2:36][N:35]([CH2:38][C:39]([F:40])([F:41])[F:42])[CH2:34][CH2:33]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)N4CCN(CC(F)(F)F)CC4)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC(=O)N4CCN(CC(F)(F)F)CC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.5 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (75.9 mg, 103 μmol) in dichloromethane (5 mL) under Ar, trifluoroacetic acid (744 mg, 0.50 mL, 6.52 mmol) was added at 25° C. After 96 h, the reaction was concentrated in vacuo and stirred in a mixture of dichloromethane/methanol/NH3OH (3:2:0.25, 5.25 mL) at 25° C. After 2.5 h, the material was concentrated and dried in vacuo (200 mTorr, 25° C.) to give a yellow solid. The solid was purified by chromatography (silica, 12 g Analogix column, 10-100% ethyl acetate in hexanes, gradient over 1 h) to give a yellow oil. The oil was dissolved in ethanol (4.5 mL, 200 proof) and cooled to 4° C. The precipitated solid was isolated by filtration and dried in vacuo (100 mTorr, 40° C.) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (36.2 mg, 54.1 μmol, 53%) as a yellow solid. MS (M)'=609; 1H NMR (DMSO-d6) δ: 12.84 (d, J=3.0 Hz, 1H), 9.03 (s, 1H), 8.40 (d, J=3.0 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.89 (s, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.39 (dd, J=2.3, 9.0 Hz, 1H), 7.20 (t, J=74.5 Hz, 1H), 5.66 (s, 2H), 3.64 (br. s, 2H), 3.47 (br. s, 2H), 3.29 (q, J=10.3 Hz, 2H), 2.77 (br. s, 2H), 2.64 (br. s, 2H), 1.51 (s, 9H).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: COc1cccc(COCCBr)c1
Solvent: CC#N
Product: COc1cccc(COCC[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)C3)c1
Product: [Br-]
Yield: 36.8 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (33.0 mg, 0.118 mmol) and 1-{[(2-bromoethyl)oxy]methyl}-3-(methyloxy)benzene (42.5 mg, 0.173 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (22.8 mg, 37%). EI-MS m/z 444 (M+) Rt (1.96 min).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>O1CCCC1>[C:16]([Si:13]([CH3:15])([CH3:14])[N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[CH:3]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Ic1c[nH]c2ncccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)n1cc(I)c2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
3-Iodo-1H-pyrrolo[2,3-b]pyridine 36 (1.11 g, 4.6 mmol) was dissolved in tetrahydrofuran (120 mL). Sodium hydride (60% dispersion in mineral oil, 0.13 g, 5.5 mmol) was added, followed by tert-butyldimethylsilyl chloride (0.85 g, 5.5 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound as a white solid (38, 100 mg, 15%).
Reaction SMILES: Cl.[CH2:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[CH2:4][N:3]1[C:10]([NH2:12])=[O:11].[CH2:13]1C2CNCC2CN1C(N)=O.C([O-])([O-])=O.[K+].[K+].CS([CH2:34][CH2:35][C:36]1[CH:52]=[CH:51][C:39]([O:40][C:41]2[S:42][C:43]3[CH:49]=[C:48](C)[CH:47]=[CH:46][C:44]=3[N:45]=2)=[CH:38][CH:37]=1)(=O)=O>C(Cl)Cl.CO.C(O)(CC)(C)C>[CH3:13][C:46]1[C:44]2[N:45]=[C:41]([O:40][C:39]3[CH:38]=[CH:37][C:36]([CH2:35][CH2:34][N:8]4[CH2:7][CH:6]5[CH2:2][N:3]([C:10]([NH2:12])=[O:11])[CH2:4][CH:5]5[CH2:9]4)=[CH:52][CH:51]=3)[S:42][C:43]=2[CH:49]=[CH:48][CH:47]=1
Reactant: Cc1ccc2nc(Oc3ccc(CCS(C)(=O)=O)cc3)sc2c1
Reactant: NC(=O)N1CC2CNCC2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CCC(C)(C)O
Product: Cc1cccc2sc(Oc3ccc(CCN4CC5CN(C(N)=O)CC5C4)cc3)nc12
Temperature: 80 °C
Yield: 5 %

Procedure:
A solution of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amide hydrochloride in 50% CH2Cl2/CH3OH was treated with DOWEX Monosphere 550A (OH) anion-exchange resin to afford the free base. The DOWEX resin was filtered and the resulting solution was concentrated and used without further purification. To a solution of this hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amide (85 mg, 0.54 mmol) and K2CO3 (116 mg, 0.84 mmol) in tert-amyl alcohol (2.6 mL) was added 2-[4-(2-methanesulfonyl-ethyl)-phenoxy]-6-methyl-benzothiazole (120 mg, 0.34 mmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered and washed with CH3OH. The resulting liquid was purified by preparative reverse phase HPLC to afford the title compound (11 mg, 5%). MS (ESI): mass calcd. for C23H26N4O2S, 422.55; m/z found, 423.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.62 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.28 (s, 4H), 7.20 (dd, J=8.3, 1.1 Hz, 1H), 4.39 (s, 2H), 3.60 (dd, J=10.2, 8.2 Hz, 2H), 3.30 (dd, J=10.0, 1.9 Hz, 2H), 2.98-2.87 (m, 2H), 2.86-2.80 (m, 2H), 2.76 (dd, J=9.3, 6.9 Hz, 2H), 2.74-2.67 (m, 2H), 2.53 (dd, J=9.3, 3.4 Hz, 2H), 2.45 (s, 3H).