Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C=O.[CH:33](O)=O>C(Cl)(Cl)Cl>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][N:12]([CH3:33])[CH2:11][CH2:10]1
Reactant: O=CO
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Agent: C=O
Solvent: ClC(Cl)Cl
Product: CN1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
The mixture of Isomer A of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepane (3 mg), paraformaldehyde (3 mg) and formic acid (2.2 mg) in chloroform (0.1 mL) was stirred at 65° C. for overnight. After cooling down, the mixture was concentrated under vacuum and filtered through anion exchange cartridge to get rid of formic acid. The crude product was purified by prep TLC with 10% methanol/89% dichloromethane/1% NH4OH to give the product as a clear sticky oil (2 mg, 67% yield).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C:11]1[N:15]=[C:14]([NH:16][C:17]2[N:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][C:26](OC)=O)=[CH:19][C:18]=2[O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[S:13][N:12]=1.[CH3:38]C([O-])(C)C.[K+].BrCC1CC1.CN(C=O)C>C1COCC1.CCOC(C)=O>[CH:25]1([CH2:24][S:23][C:20]2[CH:19]=[C:18]([O:30][C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)[C:17]([NH:16][C:14]3[S:13][N:12]=[C:11]([C@H:2]4[CH2:3][O:4][C:5]5([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]5)[O:1]4)[N:15]=3)=[N:22][CH:21]=2)[CH2:38][CH2:26]1
Reactant: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ncccc1Oc1cc(SCC2CC2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
To a solution of (S)-methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (0.428 g, 0.787 mmol) in THF (20 mL) was added potassium 2-methylpropan-2-olate (1M in THF, 2.36 ml, 2.36 mmol) and the reaction was stirred at ambient temperature for 5 minutes. (Bromomethyl)cyclopropane (0.106 g, 0.787 mmol) was added followed by DMF (5 mL) and the reaction was stirred for 1 hour at ambient temperature. The reaction was poured into EtOAc (500 mL) and the organic layer was washed with a 1:1 solution of water, 1N NaOH (100 mL total) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified over silica gel (40% EtOAc/CH2Cl2) to afford (S)—N-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.30 g, 0.586 mmol, 74.5% yield).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[C:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=1)([CH3:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C.C(Cl)Cl>C1COCC1.CCO>[C:11]([O:10][C:8](=[O:9])[C:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=1)([CH3:15])[C:6]([OH:31])=[O:5])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C(C)(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(CC(C)(C(=O)O)C(=O)OC(C)(C)C)cn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
1M NaOH (2 mL) was added to a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-methyl-malonic acid tert-butyl ester ethyl ester (0.42g, 1.03 mmol) in THF/EtOH (4 mL, 1:1) . The reaction mixture was stirred at 50° C. for 16 h. CH2Cl2 was added and the mixture was washed with 0.5 M HCl and brine and dried. Concentration under reduced pressure gave 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-methyl-malonic acid mono-tert-butyl ester (348 mg, 89%).
Reaction SMILES: I[C:2]1[CH:7]([O:8][CH3:9])[NH:6][C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.[CH3:30][C:31]1[C:39]2[S:38][CH:37]=[N:36][C:35]=2[CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[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.I[Cu]>[CH3:9][O:8][CH:7]1[NH:6][C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:3]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[C:2]1[C:37]1[S:38][C:39]2[C:31]([CH3:30])=[CH:32][CH:33]=[CH:34][C:35]=2[N:36]=1
Reactant: Cc1cccc2ncsc12
Reactant: COC1NC(N2CCOCC2)=NC(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)=C1I
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC1NC(N2CCOCC2)=NC(NC2CCCN(C(=O)OC(C)(C)C)C2)=C1c1nc2cccc(C)c2s1

Procedure:
Following the same procedure as in step 3 of Example 337 using tert-butyl (3R)-3-[[5-iodo-6-methoxy-2-(morpholin-4-yl)-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate (30 mg, 0.06 mmol, 1.00 equiv), 7-methyl-1,3-benzothiazole (15.5 mg, 0.10 mmol, 1.81 equiv), tetrakis(triphenylphosphane) palladium (12 mg, 0.01 mmol, 0.18 equiv), iodocopper (2 mg, 0.01 mmol, 0.18 equiv), and cesium Carbonate (112.8 mg, 0.35 mmol, 6.00 equiv) in N,N-dimethylformamide (2.5 mL). The crude product was purified through a silica gel column with ethyl acetate/petroleum ether (1:10-1:5) to afford the title compound as a brown solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1>>[Cl:1][S:2]([C:13]1[CH:12]=[C:11]([CH2:14][C:15](=[O:17])[CH3:16])[CH:10]=[CH:9][C:8]=1[O:7][CH3:6])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(CC(C)=O)cc1
Product: COc1ccc(CC(C)=O)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To 250 g of chlorosulfonic acid was added dropwise 50 g of 4-methoxyphenylacetone at 0°-5° C. After stirring the mixture for 4 hours at room temperature, the reaction mixture was poured into 2,500 ml of ice water and extracted three times with 500 ml of ethyl acetate. The extract was washed with water and after drying the extract with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The crude crystals obtained were recrystallized from benzene-ether to provide 32 g of 3-chlorosulfonyl-4-methoxyphenylacetone.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[CH2:4]1.[H-].[Na+].Cl[C:12]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[C:24]([CH3:31])[CH:23]=2)[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>CC(N(C)C)=O>[NH:6]1[CH2:7][CH:3]([CH2:2][O:1][C:12]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[C:24]([CH3:31])[CH:23]=3)[CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[CH2:4][C:5]1=[O:8]
Reactant: O=C1CC(CO)CN1
Reactant: Cc1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2cc3ncccc3c(OCC3CNC(=O)C3)n2)ccc1N(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
45 mg (0.38 mmol) 4-hydroxymethylpyrrolidin-2-one was placed in 1 ml dimethylacetamide and 16 mg (0.29 mmol) sodium hydride (60%) were added and the mixture was stirred for 15 min at ambient temperature. Then 100 mg (0.34 mmol) of 6.1 was added and the mixture was stirred for 2 h at 50° C. and overnight at 25° C. The reaction mixture was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[N:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]([CH3:19])[CH2:17][C:16](=[O:20])[NH:15][N:14]=2)=[CH:9][C:8]=1[OH:21])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>O>[Cl:1][C:2]1[C:3]([C:4]2[O:21][C:8]3[CH:9]=[C:10]([C:13]4[CH:18]([CH3:19])[CH2:17][C:16](=[O:20])[NH:15][N:14]=4)[CH:11]=[CH:12][C:7]=3[N:6]=2)=[CH:22][CH:23]=[C:24]([Cl:26])[N:25]=1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccc(Cl)nc2Cl)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(Cl)nc3Cl)oc2c1

Procedure:
5.8 g (0.015 mol) 2,6-dichloro-N-[2-hydroxy-4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-nicotinamide, 0.6 g para-toluenesulphonic acid and 60 ml glacial acetic acid are refluxed together for 15 h, then 40 ml glacial acetic acid are eliminated in vacuo and the residue is mixed with water. The precipitate formed is filtered off, washed with ethanol and then recrystallised from dioxane/DMF.
Reaction SMILES: [CH2:1](N)[CH2:2][NH2:3].Cl.C(O[C:9](=[NH:26])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:12]1[Cl:25])C>C(O)C.C(Cl)(Cl)Cl>[Cl:25][C:12]1[N:11]([CH2:10][C:9]2[NH:26][CH2:1][CH2:2][N:3]=2)[C:19]2[C:14]([C:13]=1[S:21]([CH3:24])(=[O:22])=[O:23])=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2
Reactant: CCOC(=N)Cn1c(Cl)c(S(C)(=O)=O)c2cc(Cl)ccc21
Reactant: NCCN
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1c(Cl)n(CC2=NCCN2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of ethylene diamine(0.065 g, 1.092 mmole) in ethanol:chloroform (30 ml, 1:1) at 0° C. under a nitrogen atmosphere was added 2-(2,5-dichloro-3-methanesulfonyl-indol-1-yl)-acetimidic acid ethyl ester hydrochloride (0.351 g, 0.91 mmole) dissolved in chloroform (5 ml). The reaction mixture was stirred at room temperature for 2 h and then evaporated to dryness. The residue was purified by column chromatography (silica gel) eluting the product with 7:93 methanol:methylene chloride with 0.1% ammonium hydroxide added. The resulting product, pure 2,5-dichloro-1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-1H-indole weighed 0.314 g (99.7% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])[CH2:8][CH2:7][CH2:6]2.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1S(=O)(=O)N=CN(C)C)CCC2
Agent: BrB(Br)Br
Product: CN(C)C=NS(=O)(=O)c1cc2c(cc1O)CCC2

Procedure:
This compound is prepared analogously to Example 1 d from 5-methoxy-6-dimethylaminomethyleneaminosulfonylindane and boron tribromide.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:5]=1[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]([C:22]1[C:27]([NH2:28])=[N:26][C:25]([NH2:29])=[C:24]([Cl:30])[N:23]=1)=[O:21])=[NH:18]>Br>[ClH:30].[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]([C:22]1[C:27]([NH2:28])=[N:26][C:25]([NH2:29])=[C:24]([Cl:30])[N:23]=1)=[O:21])=[NH:18]
Reactant: COc1ccc(CCCCNC(=N)NC(=O)c2nc(Cl)c(N)nc2N)c(OC)c1
Agent: Br
Agent: Cl
Product: N=C(NCCCCc1ccc(O)cc1O)NC(=O)c1nc(Cl)c(N)nc1N
Yield: 58.3 %

Procedure:
A vigorously stirred solution of 80 (290 mg, 0.63 mmol) in 48% HBr (20 mL) was refluxed for 4 h and then cooled. The solvent was removed at reduced pressure and the material was purified by column chromatography (silica gel, 4:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide). The fractions with product were collected and the solvent was removed under reduced pressure. The residue was treated with 3% HCl, washed with water (2×5 mL) and dried to provide 81 (79 mg, 32%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.54 (s, 4H), 2.43 (br s, 2H), 3.31 (br s, 2H), 6.12 (d, 1H), 6.32 (s, 1H), 6.78 (d, 1H), 8.86 (br s, 1H), 8.99 (br s, 1H), 9.28 (s, 1H), 10.56 (s, 1H). APCI MS m/z 394 [C16H20ClN7O3+H]+.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1.C=C>C(Cl)(Cl)Cl>[Cl:1][Si:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([Cl:4])[Cl:3]
Reactant: Cl[SiH](Cl)Cl
Reactant: CC1=CCCCC1
Agent: C=C
Solvent: ClC(Cl)Cl
Product: Cl[Si](Cl)(Cl)CC1CCCCC1
Reaction time: 144 h

Procedure:
A mixture of 20 ml trichlorosilane, 25 ml chloroform, 8.1 g 1-methylcyclohexene and 0.055 g (phenazine)PtCl2 (C2H4) was refluxed and stirred under nitrogen for 6 days. Distillation of the reaction mixture afforded 2.2 g of trichlorosilylmethylcyclohexane C6H11CH2SiCl3 which was characterized by its mass and NMR spectra.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[N:24]([CH3:25])[CH:23]=[C:22]([CH:26]=[O:27])[CH:21]=2)=[O:19])=[CH:16][CH:15]=1.O>CCOCC.CCCCCC.C1COCC1>[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[N:24]([CH3:25])[CH:23]=[C:22]([CH:26]([OH:27])[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[CH:21]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: Brc1ccncc1
Reactant: Cn1cc(C=O)cc1C(=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: Cn1cc(C(O)c2ccncc2)cc1C(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
A solution of 1.36 g (8.64 mmol) of 4-bromopyridine in 12 mL of ether was cooled to −40° C. under argon and 5.4 mL (8.64 mmol) of 1.6 M n-butyllithium in hexane was added dropwise. A solution of 1.07 g (4.3 mmol) of 5-(4-chloro-benzoyl)-1-methyl-1H-pyrrole-3-carboxaldehyde (obtained from Procedure 5) in 15 mL of THF was added dropwise (exotherm). The reaction was stirred for 5 min and poured into water and extracted with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. The residue was flash chromatographed (50%acetone/hexane). The trailing spot was concentrated and recrystallized from EtOAc to give 0.74 g (52% yield) of the title compound as a white solid: mp 145-146° C. ES-MS m/z=327 (M++H). 1H NMR (300 MHz, CDCl3) δ 2.55 (s, 1H); 4.0 (s, 3H); 5.8 (s, 1H); 6.56 (s, 1H); 6.8 (s, 1H); 7.3 (dd, 2H); 7.4 (dd, 2H); 7.75 (dd, 2H); 8.55 (dd, 2H). Anal calc'd for C18H15ClN2O2: 66.16; H, 4.63; N, 8.57. Found: C, 65.8; H, 4.65; N, 8.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:37])=[O:36])[CH:30]=2)[N:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:48]=2N=N1>CN(C)C1C=CN=CC=1.CO>[CH3:48][O:36][C:35]([C:31]1[CH:30]=[C:29]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)(=[O:21])=[O:20])[N:6]=2)[CH:34]=[CH:33][N:32]=1)=[O:37]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)O)c2)nc1OC
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Product: COC(=O)c1cc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
220 mg of 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid, product of example 21, suspended in acetontrile (10 ml) was treated at RT subsequently with 27 mg of methanol, 100 mg of 4-(dimethylamino)pyridine (DMAP) and 186 mg of benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). The mixture was stirred for 12 h at RT, then partitioned between cold diluted HCl and EtOAc. The layers were separated, the organic layer dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/MeOHc: 95/5). Combination of the purified fractions and evacuation in vacuo afforded 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid methyl ester as a white solid. ISN mass spectrum, m/e 536.2 (M−1 calculated for C25H23N5O7S: 536).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C@H:3]([OH:6])[CH2:4][OH:5].N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[OH:6][C@@H:3]([C:2]([CH3:8])([CH3:7])[CH3:1])[CH2:4][O:5][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[C@H](O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a solution of (2S)-3,3-dimethyl-butane-1,2-diol (3.1 g, 26.3 mmol) in dichloromethane (25 ml) is added pyridine (4.3 ml, 52.6 mmol). To the mixture is then added dropwise a solution of 4-toluenesulfonyl chloride (5.0 g, 26.3 mmol) in dichloromethane (25 ml) at 0° C. The reaction mixture is warmed to room temperature and stirred for additional 16 h. The reaction mixture is diluted with dichloromethane (50 ml) and washed with 10% copper(II) sulfate solution (2×30 ml). The organic layer is dried over sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 5% ethyl acetate/hexane) affording 4-methyl-benzenesulfonic acid [(2S)-2-hydroxy-3,3-dimethyl-butyl]ester (4.2 g, 14.4 mmol, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:22])[CH2:8][N:9]2[S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[N:6]([C:29](=[O:31])[CH3:30])[C@@H:7]([CH3:22])[CH2:8][N:9]2[S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H](C)Nc3ccc(Br)cc32)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(Br)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.4 %

Procedure:
A 2-L, three-necked, round bottomed flask fitted with a nitrogen inlet, overhead stirring, and thermocouple was charged with (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydroquinoxaline (45.0 g, 118 mmol), dichloromethane (900 mL), and pyridine (14.32 mL, 177 mmol). The mixture was cooled to 0° C. and acetyl chloride (10.07 mL, 142 mmol) was added slowly while maintaining the internal temperature below 10° C. The reaction mixture was held cold (ca. 30 min) and then warmed to rt. After 1 h, the reaction was diluted with dichloromethane (200 mL), and the solution was washed with 1 M aqueous HCl (2×100 mL) and water (100 mL). The organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (eluting with 3:1 dichloromethane-ethyl acetate) to afford (S)-1-(6-bromo-2-methyl-4-tosyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (54.15 g, 108%), which contained 4.1 wt % ethyl acetate, as a colorless to yellow oil. MS (ESI, pos. ion) m/z 424 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:35]>ClCCl.CO.C(OCC)C>[ClH:35].[F:8][C:6]1[CH:5]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]2[CH2:22][CH:23]4[NH:27][CH:26]([C:15]3=2)[CH2:25][CH2:24]4)(=[O:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cc(F)cc(F)c4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: Cn1c2c(c3cc(S(=O)(=O)c4cc(F)cc(F)c4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of step A in dichloromethane (0.9 mL) and methanol (0.1 mL) was added 2M HCl in diethyl ether (5 mL). The reaction mixture was stirred at ambient temperature overnight, filtered, washed with diethyl ether and dried in vacuo to give 2-(3,5-difluorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (15 mg, 50%, AUC HPLC 98.0%) as an off-white solid: mp 230-235° C. dec; 1H NMR (CD3OD, 300 MHz) δ 8.32 (d, J=1.8 Hz, 1H), 7.77 (dd, J=8.7, 1.8 Hz, 1H), 7.57-7.61 (m, 3H), 7.20-7.28 (m, 1H), 5.32 (d, J=4.8 Hz, 1H), 4.55 (br s, 1H), 3.73 (s, 3H), 3.49 (dd, J=17.4, 4.5 Hz, 1H), 3.25-3.40 (m, 1H), 3.08 (d, J=17.4 Hz, 1H), 2.26-2.48 (m, 2H), 1.96-2.00 (m, 1H); ESI MS m/z 389 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22](N)=[O:23])[CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:25].[K+]>C(O)C>[C:10]1([C:7]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])=[O:23])[CH:17]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH3:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [OH-]
Reactant: CCC(c1ccccc1)(c1ccccc1)c1ccnc(C(N)=O)c1
Agent: [K+]
Solvent: CCO
Product: CCC(c1ccccc1)(c1ccccc1)c1ccnc(C(=O)O)c1

Procedure:
Dissolve 3.8 g. of 4-(1,1-diphenylpropyl)-picolinamide in 50 ml. of ethanol, add 100 ml. of 10% aqueous potassium hydroxide and heat the resulting mixture at reflux overnight. Remove the ethanol under reduced pressure, add water to the residue and adjust to about pH 5 with 10% aqueous hydrochloric acid. Filter the resulting solid and crystallize the precipitate from ethanol to obtain thereby the compound of this example, yield -- 1.6 g., m.p. 191°-193° C.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCC[CH2:23]1.CC(C)([O-])C.[K+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[CH2:23])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 4-(diphenylamino)benzaldehyde (20.06 g, 73 mmol, Fluka Chemical Co., Milwaukee, Wis.), methyltriphenyl phosphonium bromide (26.22 g, 73 mmol) and dry tetrahydrofuran (450 mL) under nitrogen was added a 1M solution of potassium t-butoxide in tetrahydrofuran (80 mL, 80 mmol) over 5 minutes. The mixture was stirred for 17 hours at room temperature. Water (400 mL) was added and the tetrahydrofuran was removed under reduced pressure. The mixture was extracted with ether, and the combined organic layers were dried over MgSO4 and concentrated under vacuum. The crude solid was purified by column chromatography on silica gel using a 50/50 mixture of methylene chloride and hexane to give a yellow solid that was further recrystallized once from hexane (15.37 g, 78%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([NH2:23])=[N:21][NH:20][C:17]3=[CH:18][N:19]=2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH:1]1([C:4]([N:20]2[C:17]3=[CH:18][N:19]=[C:14]([C:11]4[CH:12]=[N:13][C:8]([CH3:7])=[CH:9][CH:10]=4)[CH:15]=[C:16]3[C:22]([NH:23][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[N:21]2)=[O:5])[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2cc3c(N)n[nH]c3cn2)cn1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: Cc1ccc(-c2cc3c(NC(=O)C4CC4)nn(C(=O)C4CC4)c3cn2)cn1

Procedure:
Cyclopropanecarbonyl chloride (186 mg, 1.776 mmol) was added to a stirred solution of 5-(6-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine (200 mg, 0.888 mmol) in anhydrous pyridine (5 mL) and the reaction was heated under reflux for 16 hours. The solvent was removed in vacuo, and the residue chromatographed on silica gel using 10% v/v methanol in dichloromethane as eluent to afford the title compound as a solid.