Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]3[N:22]=[C:21]4[C:16]([C:17](=[O:31])[C:18]([C:28]([OH:30])=[O:29])=[CH:19][N:20]4[C:23]45[CH2:27][CH:25]([CH2:26]4)[CH2:24]5)=[CH:15][C:14]=3[F:32])[CH2:8]2)C=CC=CC=1.[CH3:33]S([O-])(=O)=O>>[CH3:1][CH:7]1[N:12]([CH3:33])[CH2:11][CH2:10][N:9]([C:13]2[N:22]=[C:21]3[C:16]([C:17](=[O:31])[C:18]([C:28]([OH:30])=[O:29])=[CH:19][N:20]3[C:23]34[CH2:27][CH:25]([CH2:26]3)[CH2:24]4)=[CH:15][C:14]=2[F:32])[CH2:8]1
Reactant: CS(=O)(=O)[O-]
Reactant: O=C(O)c1cn(C23CC(C2)C3)c2nc(N3CCNC(c4ccccc4)C3)c(F)cc2c1=O
Product: CC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C23CC(C2)C3)CCN1C

Procedure:
7-(3-phenyl-1-piperazinyl)-1-(bicyclo[1.1.1]pent-1-yl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:32]([CH3:34])[CH3:33])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)Br
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC(C)C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To a solution of 0.20 g (0.468 mmol) of the product of Example 37 dissolved in 5.0 mL of DMF was added 0.26 mL (2.81 mmol) of 2-bromopropane and 1.16 g (8.43 mmol) of potassium carbonate. The reaction mixture was then heated to 80 degrees for 18 h, cooled to room temperature, diluted with ether and washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc-Hexanes (1:3) to provide 0.198 g (90%) of the desired product as a colorless oil. Electrospray Mass Spec: 470.3 (M+H)+
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15](=[O:32])[NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][CH2:50][C@@H:51]([C:52]#[N:53])[N:43]2[C:42]1=[O:54]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])=[O:32])[C:9]([NH:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][CH2:50][C@@H:51]([C:52]#[N:53])[N:43]2[C:42]1=[O:54])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: N#C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Product: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C#N)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7S,10aS)-7-cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-2-oxo-1-o-tolylazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 71 (10 mg, 0.019 mmol) and Intermediate 36 (5.2 mg, 0.020 mmol) to give a white solid (8.0 mg, 57% yield). Anal. Calcd. for C43H51N5O4S m/z 733.7. found: 734.3 (M+H)+; 1H NMR (400 MHz, CDCl3) (Rotamers) δ ppm 7.39-6.79 (16H, m), 5.35 (1H, d, J=3.8 Hz), 5.24 (1H, d, J=4.9 Hz), 5.02-4.90 (1H, m), 4.87-4.77 (1H, m), 4.07-3.88 (1H, m), 3.58-3.29 (1H, m), 3.02-2.86 (1H, m), 2.85-2.70 (4H, m), 2.66-2.36 (3H, m), 2.21-2.09 (5H, m), 2.05-1.47 (14H, m), 1.46-1.15 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[CH2:3][C@@H:4]([NH:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.O1CCCC1.[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:37])[CH2:3][C@@H:4]([NH:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCNC(=O)c1ccc(N[C@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C[C@@H](Nc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 504.4 %

Procedure:
A round bottom flask was charged with (R)-methyl 3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido)propanoate (6.26 g, 10.2 mmol), tetrahydrofuran (60 mL) and methanol (60 mL). 1.0N NaOH (18.3 mL, 18.3 mmol) was added and the resulting solution was stirred at room temperature for 15 min. The organic solvents were removed under reduced pressure and the resulting crude was diluted with water. 10% Citric acid was added to acidify the solution to pH˜3. A white precipitate formed. After stirring for 30 minutes at room temperature, the solid was filtered off and dried under vacuum. Purification by column chromatography (0-10% methanol/dichloromethane) provided (R)-3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido)propanoic acid (25.7 g, 76.4%) as a white solid. 1H NMR (400 MHz, (CD3)2SO, δ): 0.91 (d, J=6.44 Hz, 3 H) 0.95 (d, J=6.44 Hz, 3 H) 1.48-1.59 (m, 1 H) 1.61-1.71 (m, 1 H) 1.72-1.82 (m, 1 H) 2.44 (t, J=7.12 Hz, 2 H) 3.34-3.42 (m, 2 H) 5.10 (br. s., 1 H) 6.52 (d, J=8.78 Hz, 1 H) 7.46-7.51 (m, 2 H) 7.57 (d, J=8.19 Hz, 1 H) 7.63-7.69 (m, 2 H) 7.74 (dd, J=8.88, 2.44 Hz, 1 H) 7.76-7.81 (m, 2 H) 7.83-7.89 (m, 2 H) 8.15 (t, J=5.46 Hz, 1 H) 8.40 (d, J=2.34 Hz, 1 H) 12.18 (br. s., 1 H). MS (M+1): 500.4.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:22][O:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)Cc1cccc(Oc2ccccc2Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(CC(=O)O)cccc1Oc1ccccc1Cl
Yield: 67.6 %

Procedure:
A mixture of 2-[2-hydroxy-3-(2-chlorophenoxy)phenyl]acetic acid (1.9 g), methyl iodide (2.3 g) and potassium carbonate (2.2 g) in acetone (40 ml) was refluxed under heating for 4.5 hrs. After cooling, the reaction mixture was filtered. The filtrate was evaporated, and the oily residue was dissolved in methanol (30 ml). To the solution was added potassium hydroxide (1 g), and the mixture was refluxed under heating for 30 minutes. After cooling, the reaction mixture was evaporated and the residue was dissolved in water. The aqueous solution was washed with diethyl ether, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was recrystallized from a mixture of benzene and n-hexane to give 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]acetic acid (1.35 g). mp 87°-92° C.
Reaction SMILES: [Cu]C#N.[C:4]([Mg]Cl)([CH3:7])([CH3:6])[CH3:5].Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][N:12]=1.O>C1COCC1>[CH3:5][C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][N:12]=1)([CH3:7])[CH3:6]
Reactant: Brc1ccc(OCc2ccccc2)cn1
Reactant: CC(C)(C)[Mg]Cl
Agent: N#C[Cu]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCc2ccccc2)cn1
Reaction time: 0.25 h

Procedure:
To a stirred solution of copper (I) cyanide (18.31 g) in dry THF (400 ml) was added, at −78 C, tertbutylmagnesium chloride (1M in THF, 409 ml). The reaction mixture was stirred at this temperature for 15 min before slowly adding a solution of 2-bromo-5-[(phenylmethyl)oxy]pyridine (13.5 g) in THF. This was stirred for 2 h at −78 C before warming to 25-30 C and stirring for a further 20 h. The reaction mixture was poured into water and extracted with ethyl acetate. This was concentrated in vacuo and purified through silica, eluting with 0-2% ethyl acetate in hexane. Appropriate fractions were combined and concentrated in vacuo to yield the title compound, 6.3 g
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17]CC)=O)=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.Cl[C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:8]([C:6]1[CH:7]=[C:2]2[C:3]([C:15]([OH:17])=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21](=[O:28])[NH:1]2)=[N:4][CH:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1N
Reactant: CCOC(=O)CC(=O)Cl
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 3-amino-5-benzylpyridine-2-carboxylate and ethyl 3-chloro-3-oxopropionate employing methods similar to those described in Example 1, Steps 9-10. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.72 (1H, br s), 8.24 (1H, br s), 7.36-7.23 (6H, m), 4.14 (2H, q, J=7 Hz), 4.06 (2H, s), 1.22 (3H, t, J=7 Hz); ES+ MS: 325 (M+H+, 75), 347 (M+Na+, 26); Anal. Calcd for C18H16N2O4: C, 53.61; H, 3.99; N, 6.94. Found: C, 53.40; H, 3.92; N, 6.92.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:20][O:14][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[N:11]=1
Reactant: O=c1nc(-c2ccccc2Cl)c2ccsc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(-c2ccccc2Cl)c2ccsc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.0 g of 4-(o-chlorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 80 ml of dimethylformamide is added 0.82 g of 63% sodium hydride. The resulting mixture is stirred at room temperature for 30 minutes. Then, 6.48 g of methyl iodide in 33 ml of dimethylformamide is added dropwise thereto. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-(o-chlorophenyl)-thieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 172.5° - 174.5°C (after recrystallization from ether). From the second fraction, 1-methyl-4-(o-chlorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 225° - 226°C (after recrystallization from chloroform-ethanol). From the third fraction, 3-methyl-4-(o-chlorophenyl)-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 190° - 192°C (after recrystallization from ethanol-ether).
Reaction SMILES: C(OC(=O)NC1C=CC(Cl)=CC=1[N+]([O-])=O)(C)(C)C.[CH3:19][S:20](C1C2C(=CC=CC=2)NC=1)(=[O:22])=[O:21].[Cl:32][C:33]1[CH:50]=[CH:49][C:36]2[N:37]([CH2:42][CH2:43]CS(C)(=O)=O)[C:38]([CH2:40][Cl:41])=[N:39][C:35]=2[CH:34]=1>>[Cl:32][C:33]1[CH:50]=[CH:49][C:36]2[N:37]([CH2:42][CH2:43][S:20]([CH3:19])(=[O:22])=[O:21])[C:38]([CH2:40][Cl:41])=[N:39][C:35]=2[CH:34]=1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1c[nH]c2ccccc12
Agent: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Product: CS(=O)(=O)CCn1c(CCl)nc2cc(Cl)ccc21

Procedure:
5-Chloro-2-chloromethyl-1-(2-methanesulfonyl-ethyl)-1H-benzoimidazole was prepared in analogy to Example 1-2 by using (4-chloro-2-nitro-phenyl)-carbamic acid tert-butyl ester as starting material instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole. MS obsd. (ESI+) [(M+H)+] 308.1.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(OCC)(=O)C>[NH:1]1[C:5]2=[N+:6]([O-:18])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: CCOC(C)=O
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 0 °C

Procedure:
1H-pyrrolo[2,3-b]pyridine (2.8 g, 24 mmol) was dissolved in ethyl acetate (24 mL) and cooled to 0° C. A solution of 3-chloroperbenzoic acid (77%, 6.7 g, 30.1 mmol) in ethyl acetate (24 mL) was added drop-wise then the reaction mixture warmed to 25° C. over 16 h. The reaction mixture was cooled to 0° C., filtered, and the solids dried to give crude 1H-pyrrolo[2,3-b]pyridine 7-oxide, 3-chlorobenzoic acid complex (4.1 g, 58%) as an off-white solid. This was used directly in the next step without purification. LCMS (EI/CI) m/z: 135 [M+H].
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.N[CH:32]([CH2:57][CH:58]([F:60])[F:59])[C:33](=[O:56])[C:34](=[P:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:35]#[N:36]>ClCCl>[NH:1]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[F:60][CH:58]([F:59])[CH2:57][CH2:32][C:33](=[O:56])[C:34](=[P:37]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:35]#[N:36]
Reactant: N#CC(C(=O)C(N)CC(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: N#CC(C(=O)CCC(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Synthesis of compound 15 (see scheme 7) Boc-Leu-OH (1.16 g, 5 mmol) was dissolved in dichloromethane (50 mL) and EDC (1.05 g, 5.5 mmol) and HOBt (743 mg, 5.5 mmol) were added. The resulting solution was cooled to 0° C. and (±)-4-Amino-6,6-difluoro-3-oxo-2-triphenylphosphoranylidene-hexanenitrile (2.32 g, 5.5 mmol) was added in one portion. The ice bath was removed and the mixture stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (100 mL) and washed successively with 1 N aqueous HCl, water, saturated aqueous NaHCO3 and brine. Drying (Na2SO4) and evaporation gave 2.7 g (85%) of Boc-Leu-6,6-difluoro-3-oxo-2-triphenylphosphoranylidene-hexanenitrile as a yellowish foam. The foregoing compound (2.7 g, 4.2 mmol) was dissolved in dichloromethane/methanol (40 ml, 7:3, v/v) and cooled to −78° C. Ozone was bubbled through the solution until the blue color remained. The solution was then purged with nitrogen and 12 mL of MeOH were added, the resulting solution was stirred at −78° C. for 30 min. and at room temperature for 2 h. Evaporation gave a light yellow oil, which was dissolved in MeOH (6 mL) and the resulting solution was cooled to 0° C. After addition portionwise of NaBH4 (159 mg, 4.2 mmol) the resulting reaction mixture was stirred at 0° C. for 2 hours, poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine and dried (Na2SO4). Evaporation gave a solid which was purified by flash chromatography (PE/ethyl acetate 3:2) to give 832 mg (50%) of the Boc protected dipeptide hydroxyester.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:23]([CH3:31])([CH3:30])[O:24][SiH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:4]([N:8]2[CH:17](O)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:19]4[CH2:21][CH2:20]4)[CH:14]=3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:23]([CH3:31])([CH3:30])[O:24][SiH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:4]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:19]4[CH2:20][CH2:21]4)[CH:14]=3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(Br)cccc1N1C(=O)c2ccc(C3CC3)cc2CC1O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1c(Br)cccc1-n1ccc2cc(C3CC3)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 2-[3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-cyclopropyl-3-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (3.52 g, 7.00 mmol) and triethylamine (4.0 mL, 29 mmol) in 50 mL of anhydrous CH2Cl2 was added 0.85 mL of methanesulfonyl chloride. Purged the flask with nitrogen and stirred at room temperature overnight. Added 25 mL of CH2Cl2 and 50 mL of water and separated phases. Washed the organic phase with 50 ml brine. Dried the solution over MgSO4 and concentrated in vacuo. Purified the residue by flash chromatography (gradient elution, 0 to 50% EtOAc/hexane) to obtain 2-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-cyclopropyl-2H-isoquinolin-1-one as an amber resin (2.90 g, 5.99 mmol). MS (ESI) 484, 486 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]#[N:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH2:22][CH3:23])([C:10]2=[O:20])[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1.C(O)C.Cl.[OH-].[Na+].[Cl-].[NH4+:32]>C(Cl)(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18](=[NH:32])[NH2:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH2:22][CH3:23])([C:10]2=[O:20])[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC#N)c(Cl)c1Cl)C2=O
Reactant: [NH4+]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC(=N)N)c(Cl)c1Cl)C2=O
Reaction time: 16 h

Procedure:
[(5,6-Dichloro-3,9-dioxo-9a-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetonitrile (3.49 g, 10 mMole), chloroform (40 ml) and ethanol (650 mg, 11 mMole) are united and saturated with hydrogen chloride gas at 0° C. The mixture is stirred for 16 hours and then basified with 10 normal sodium hydroxide solution. The chloroform layer is separated, washed with water, dried over K2CO3, and evaporated in vacuo. The residue is dissolved in ethanol (30 ml) and water (5 ml) added. The mixture is stirred and treated with ammonium chloride (700 mg, 12 mMole). After stirring at ambient temperature for 4 hours, the mixture is filtered, the filtrate evaporated to near dryness in vacuo, and the residue treated with acetone (50 ml). The solid that separates is removed by filtration, washed with acetone, dried, and recrystallized from a mixture of ethanol and ether to give 2-[(5,6-dichloro-3,9-dioxo-9a-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]ethanimidamide hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH2:10][C:11]1([CH2:19][C:20]#[C:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13][CH2:12]1.CCOC(C)=O.CCCCCC>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:8]=[C:9]1[CH2:10][C:11]3([CH2:12][O:13][C:14]([CH3:18])([CH3:17])[O:15][CH2:16]3)[CH2:19][C:20]1=[C:21]2[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC1(C)OCC(CC#CC(=O)C(C)(C)C)(CC=Cc2ccccc2Cl)CO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Clc1ccccc1Cl
Product: CC1(C)OCC2(CO1)Cc1cc3c(Cl)cccc3c(C(=O)C(C)(C)C)c1C2
Yield: 47 %

Procedure:
To a 10-20 mL microwave irradiation vial equipped with a stir bar was added compound 4b (0.21 g, 0.54 mmol) in 1,2-dichlorobenzene (10 mL). The reaction was irradiated with stirring at 180° C. for 45 min until complete by TLC (AcOEt/n-hexane 2:8). The solution was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene and then AcOEt/n-hexane 2:8 to collect the pure product. The title compound was isolated as a light yellow solid in a 47% yield (0.098 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1ccncc1
Agent: Cl
Product: Clc1ccc(-c2nn(Cc3ccncc3)c3c2CCNCC3)cc1
Yield: 19.7 %

Procedure:
The title compound (0.02 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 4-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C19H19ClN4, 338.13. found, m/z 339.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49-8.48 (m, 2H), 7.43-7.41 (m, 2H), 7.33-7.31 (m, 2H), 6.90-6.89 (m, 2H), 5.28 (s, 2H), 2.92-2.87 (m, 2H), 2.75-2.73 (m, 1H), 2.66-2.64 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29]C(=O)OC(C)(C)C)=[CH:28][C:22]=2[S:21](=[O:38])(=[O:37])[N:20]=1.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:3]3[C:4](=[O:18])[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]4[C:11]([C:2]=3[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[N:20][S:21](=[O:38])(=[O:37])[C:22]=2[CH:28]=1
Reactant: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 99 %

Procedure:
A solution of Example 40G (3.24, 6.00 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (2.86 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.42 m, 1 H) 0.74 m, 7 H) 1.32 m, 1 H) 1.58 (m, 3H) 2.15 m, 2 H) 7.07 m, 2 H) 7.51 m, 2 H) 7.77 m, 2 H) 8.16 m, 1 H) 13.57 (m, 1 H). MS (ESI−) m/z 438 (M−H)−.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]2[N:32]=[C:31]3[NH:33][N:34]=[C:35]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([S:42][CH3:43])[N:37]=4)[C:30]3=[CH:29][N:28]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl.CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]2[N:32]=[C:31]3[NH:33][N:34]=[C:35]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([S:42]([CH3:43])=[O:9])[N:37]=4)[C:30]3=[CH:29][N:28]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2n[nH]c3nc(NCC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NCC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
m-CPBA (339 mg, 1.98 mmol) was added slowly to a solution of 4-{[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (from Example 14 supra) (450 mg, 0.99 mmol) in a mixture of dichloromethane and methanol (80 mL, 1:1). The reaction mixture was stirred at room temperature for 20 minutes. The solvent was then removed under reduced pressure and the solid was purified by column chromatography (silica gel, 15 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford 4-{[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester. (Yield 150 mg, 32.3%).