Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+].[CH3:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[NH2:6].[NH4+].[C:13](=S)([S-:15])N.ClC(OCC)=O>O.C(=S)=S>[CH3:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[N:6]=[C:13]=[S:15]
Reactant: NC(=S)[S-]
Reactant: Cc1cccc(C)c1N
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: S=C=S
Product: Cc1cccc(C)c1N=C=S
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 55.2 %

Procedure:
745 grams (9.8 moles) of carbon disulfide and 1230 milliliters (ml) of concentrated ammonium hydroxide was added to a 5 liter, 3-neck flask fitted with a mechanical stirrer, teflon clad thermocouple, and an additional funnel. The contents of the flask were cooled to 0° C. by use of an ice bath. Then with rapid stirring, 1,008 grams of 2,6-dimethylaniline was added drop wise to the contents of the flask. The temperature was maintained below 10° C. by controlling the rate of addition. It is preferable to maintain the temperature in the range of about 10° C. to avoid a run away reaction (which run away begins to occur at a temperature of about 30° C. and is accompanied by a loss of ammonium (NH3) and carbon disulfide (CS2) gas). The addition took approximately 45 minutes. The reaction mixture (orange-red in color) was allowed to stir for an additional four hours, during which time a dithiocarbamate salt crystalized. The salt crystals were collected by suction filtration using a Buchner funnel, and were allowed to suck dry on the aspirator. The crystaline salt was placed in a 12-L flask fitted with a mechanical stir, thermo couple, and an addition funnel, and 5 liters of water with 2-propanol (water to propanol ratio of which ranged between 1:1 and 3:1 by volume, respectively) was added. Ethyl chloroformate (890.8 grams; 8.21 moles) was added dropwise to the stirred slurry at a rate such that the temperature did not rise above 40° C.; a cooling bath was used to help control the temperature. The addition funnel was replaced by a condenser, and the reaction mixture was heated to between 60° and 70° C. and maintained at this temperature for 1 hour. The reaction mixture was cooled to ambient temperature and then 1 liter of water was added. The layers were separated, and the bottom layer (2,6-dimethylphenylisothiocyanate) was washed with 200 ml of water and then dryed over anhydrous sodium sulfate. Distillation under vaccuum (125° Centigrade at about 3 torr.) gave 949 grams (55.2% yield on total theoretical basis by weight) of 2,6-dimethylphenylisothiocyanate. The intermediate product is filtered to remove any solid by-product prior to use in next step. The product was used directly in the next step of the synthesis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:24]=[O:25])=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[O-:26]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:24]([OH:26])=[O:25])=[C:11]([CH:21]([CH3:22])[CH3:23])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ncco3)c2c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ncco3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure D, ethyl3-formyl-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-6-carboxylate (Compound 38, 240 mg, 0.70 mmol) in t-BuOH (20 ml), 2-methyl-2-butene (2.0 ml) was added a solution of NaH2PO4 (1.69 g, 14.0 mmol) and NaClO2 (80%, 1.27 g, 14.0 mmol) in H2O (4 ml). The mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→55% EtOAc-hexanes) to yield the title compound as a light tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]=[C:21]1[NH:27][C:26]2[CH:28]=[C:29]([C:32](O)=[O:33])[CH:30]=[CH:31][C:25]=2[C:24](=[O:35])[NH:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:29]1[CH:30]=[CH:31][C:25]2[C:24](=[O:35])[NH:23][CH2:22][C:21](=[O:20])[NH:27][C:26]=2[CH:28]=1)=[O:33]
Reactant: O=C1CNC(=O)c2ccc(C(=O)O)cc2N1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)NC(=O)CNC2=O

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2,5-Dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic acid. MS: 462.3 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[O:11]C.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[C:7]([OH:8])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: COc1ccc(F)c(OC)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(F)c(O)c1F
Reaction time: 36 h
Yield: 90.7 %

Procedure:
A solution of Compound 3 (0.64 g, 3.7 mmol) in dichloromethane (0.3M, anhydrous) at room temperature under nitrogen is treated with boron tribromide solution (3.0 equivalents, 1.0M in dichloromethane, Aldrich or Fluka) via syringe over five minutes. The reaction is monitored by TLC, and takes 24-48 hours to reach completion; an additional 0.5 equivalents of boron tribromide solution is sometimes necessary to drive the reaction to completion. The reaction mixture is carefully quenched with water, and the resulting mixture is stirred until all precipitate dissolves. The resulting solution is extracted twice with ether. The ether extract is washed twice with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure and purified by sublimation to yield 0.49 g (90%) of Compound 4 as a colorless crystalline solid: m.p. 100°-101° C.; 1H NMR (CDCl3) 8.99 (s, 1H), 8.62 (s, 1H), 6.32 (td, 1H), 6.05 (m, 1H); 19F (CDCl3) 145.4 (m, 1F), 156.0 (m, 1F). Anal. calc. for C6H4O2F2 ; C, 49.33; H, 2.76. Found: C, 48.96; H, 3.21; N, 0.028.
Reaction SMILES: NC1C=C(C)C(OC2C=C3C(=CC=2)NN=C3CCC)=C(C)C=1.C(N(CC)CC)C.[CH2:30]([O:32][C:33](=[O:65])[C:34]([NH:36][C:37]1[CH:62]=[C:61]([CH3:63])[C:40]([O:41][C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[N:47](C(=O)C(OCC)=O)[N:46]=[C:45]3[CH2:58][CH2:59][CH3:60])=[C:39]([CH3:64])[CH:38]=1)=[O:35])[CH3:31]>>[CH3:63][C:61]1[CH:62]=[C:37]([NH:36][C:34](=[O:35])[C:33]([O:32][CH2:30][CH3:31])=[O:65])[CH:38]=[C:39]([CH3:64])[C:40]=1[O:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[NH:47][N:46]=[C:45]2[CH2:58][CH2:59][CH3:60]
Reactant: CCCc1nn(C(=O)C(=O)OCC)c2ccc(Oc3c(C)cc(NC(=O)C(=O)OCC)cc3C)cc12
Agent: CCCc1n[nH]c2ccc(Oc3c(C)cc(N)cc3C)cc12
Solvent: CCN(CC)CC
Product: CCCc1n[nH]c2ccc(Oc3c(C)cc(NC(=O)C(=O)OCC)cc3C)cc12
Yield: 40 %

Procedure:
Analogously to the procedure of Example 5, starting from 34 mg (0.115 mmol) of 5-(4-amino-2,6-dimethylphenoxy)-3-propyl-1H-indazole, 11.6 mg (0.115 mmol) of triethylamine and 15.7 mg (0.115 mmol) of ethyl oxalyl chloride, 18 mg, (32%) of ethyl [5-(4-{[ethoxy(oxo)acetyl]amino}-2,6-dimethylphenoxy)-3-propyl-1H-indazol-1-yl](oxo)acetate (Example 8) are obtained. Moreover, 18 mg, (40%) of ethyl ({3,5-dimethyl-4-[(3-propyl-1H-indazol-5-yl)oxy]phenyl}amino)(oxo)acetate (Example 8a) are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C(O[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(C)(C)C>CCO.[Pd]>[CH2:14]([O:13][C:11]([C@H:10]1[C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][N:8]([C:28]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:34])[CH2:9]1)=[O:12])[CH3:15]
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OCC
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC

Procedure:
A mixture of (3S*,4S*)-1-benzyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester (82.8 g, 271.14 mmol), di-tert-butylcarbonate (88.76 g, 406.71 mmol) and Pd/C 10% (8 g) in EtOH (1.5 L) is stirred under hydrogen atmosphere. The crude material is filtered over a pad of Celite and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/acetone 100:0 to 95:5). TLC, Rf (CH2Cl2/acetone 95:5)=0.51. MS (LC-MS): 216.2 [M+H-Boc]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4](Cl)[N:3]=1.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.CN1CCCC1=O.Cl>C(OCC)C.O1CCOCC1>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[N:3]=1
Reactant: Nc1nc(Cl)nc(Cl)c1Cl
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Nc2nc(N)c(Cl)c(Cl)n2)cc1
Temperature: 145 °C
Yield: 6.8 %

Procedure:
To a flask under Argon was added 4-amino-2,5,6-trichloropyrimidine (0.08564 mol), 4-amino-benzonitrile (0.1071 mol), 1-methyl-2-pyrrolidinone (17 ml) and HCl in diethylether (1M; 85.6 ml). The mixture was placed in an oil bath at 130° C. under a stream of nitrogen until the ether was gone. An additional 10 ml of 1-methyl-2-pyrrolidinone was added. The mixture was heated at 145° C. for 16 hours under argon. 1,4-Dioxane was added. The mixture was refluxed, cooled, then filtered. The filtrate was evaporated. The residue was dissolved in CH2Cl2, washed with 1 N NaOH, then filtered. The solid was dissolved in 2-propanone, evaporated onto silica gel, and chromatographed using 1-3% 2-propanone in hexane as eluent. The pure fractions were collected and the solvent was evaporated, yielding 1.63 g (6.8%) of 4-[(4-amino-5,6-dichloro-2-pyrimidinyl)amino]benzonitrile (interm. 12).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:15][C:14]([F:16])([F:17])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:3][C:2]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 75 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and morpholine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 75%; MS: m/z=419 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([NH:8][C:9]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]([NH:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[CH:27][C:21]=3[N:20]=2)=[O:17])=[O:10])[CH:7]=1.[ClH:42]>CO.O1CCOCC1>[ClH:42].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([NH:8][C:9]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]([NH:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([N:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[CH:27][C:21]=3[N:20]=2)=[O:17])=[O:10])[CH:7]=1
Reactant: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[nH]1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cc(N3CCNCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,1-dimethylethyl 4-(2-{[(4-{[(5-bromo-2-methylphenyl)amino]carbonyl}-1H-imidazol-5-yl)carbonyl]amino}-1H-benzimidazol-5-yl)piperazine-1-carboxylate (2.5 g, 4 mmol) in methanol (100 mL) was added 4 N hydrogen chloride in 1,4-dioxane (20 mL). The solution was stirred at room temperature for 48 hours. The resulting suspension was filtered to give 2.0 g of N4-(5-bromo-2-methylphenyl)-N5-(5-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-imidazole-4,5-dicarboxamide hydrochloride. 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H), 12.50 (br s, 1H), 11.20 (br s, 1H), 9.28 (d, 1H), 9.00 (d, 1H), 8.39 (s, 1H), 7.86 (s, 1H), 7.60 (d, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 7.21 (s, 1H), 7.03 (d, 1H), 4.23 (br s 2H), 3.94 (m, 2H), 3.33 (m, 2H), 2.91 (m, 2H), 2.29 (s, 3H), 2.11 (m, 1H), 1.94 (m, 2H), 1.54 (m, 2H). MS (EI): 553 (MH+).
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][C:8]3([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[NH:14][CH2:13][CH2:12][N:9]3[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:23][N:24](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]23[NH:14][CH2:13][CH2:12][N:9]2[C:10](=[O:11])[C:5]2[N:6]([C:2]([C:23]#[N:24])=[CH:3][CH:4]=2)[CH2:7]3)=[CH:16][CH:17]=1
Reactant: COc1ccc(C23Cn4c(Br)ccc4C(=O)N2CCN3)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc(C23Cn4c(C#N)ccc4C(=O)N2CCN3)cc1
Temperature: 160 °C
Yield: 71 %

Procedure:
8-bromo-10a-(4-methoxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (50 mg, 0.14 mmol), zinc cyanide (24 mg, 0.20 mmol) and palladium(0) tetrakistriphenylphosphine (32 mg, 0.03 mmol) were suspended in dry DMF (2.5 mL) in a microwave vial flushed with argon. The mixture was heated in the microwave at 160° C. for 20 minutes. Water was added and the mixture extracted with CH2Cl2. The organic layers were dried (MgSO4), filtrated and concentrated in vacuo. The resulting residue was purified by flash chromatography (Biotage SP4 12 g cartridge, gradient 0-10% MeOH in CH2Cl2) to give 10a-(4-methoxyphenyl)-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-8-carbonitrile as a brown solid (45 mg, yield 71%) ESI-MI m/z [M+H]+ 309.1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>CN(C=O)C.C(OCC)(=O)C>[CH:17]1([CH2:16][O:8][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]=2)[CH2:19][CH2:18]1
Reactant: Oc1ccc(I)cn1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1ccc(OCC2CC2)nc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
To a solution of 5-iodopyridin-2-ol (5.32 g, 24.0 mmol) in DMF (50 mL) were added cesium carbonate (23.4 g, 72.0 mmol) and (bromomethyl)cyclopropane (4.67 mL, 48.2 mmol), and the mixture was stirred at 60° C. for 15 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed three times with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:4) to give the title compound (2.17 g, yield 32%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=1)[CH2:7]2.C([SiH](CC)CC)C.[C:69]([OH:75])([C:71]([F:74])([F:73])[F:72])=[O:70]>C(Cl)Cl>[OH:75][C:69]([C:71]([F:74])([F:73])[F:72])=[O:70].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([S:27]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)(=[O:28])=[O:29])=[CH:25][CH:26]=4)[N:19]=3)[NH:14][CH:13]=1)[CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(-c3cnc4c(n3)c(N3Cc5cccc(Cl)c5C3=O)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(Cl)cccc2CN1c1c[nH]c2ncc(-c3ccc(S(=O)(=O)C4CCNCC4)cc3)nc12
Reaction time: 8 h
Yield: 59 %

Procedure:
tert-butyl 4-[4-[7-(7-chloro-1-oxo-isoindolin-2-yl)-5-trityl-pyrrolo[2,3-b]pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (186 mg, 0.2187 mmol) dissolved in DCM (2 mL) and triethylsilane (175 μL, 1.094 mmol) then TFA (0.3 mL) added under N2. Reaction mixture stirred overnight and residue azeotroped with DCM (×2) then purified by hplc. Product isolated as the TFA salt (80 mg, 59%); 1H NMR (400 MHz, DMSO) δ 1.72 (2H, brdq), 2.08 (2H, brd), 2.89 (2H, brq), 3.37 (2H, partly obsc brd), 3.63-3.70 (1H, partly obsc m), 5.49 (2H, s), 7.59 (1H, d), 7.70 (1H, t), 7.74 (1H, t), 7.99 (2H, d), 8.10-8.26 (1H, m), 8.55-8.58 (4H, m), 9.11 (1H, s), 12.42 (1H, d) ppm; MS (ES+) 508.0.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][C:6]=2[S:5][CH:4]=1.[C-:18]#[N:19].[Na+].Cl>CN(C=O)C>[C:18]([CH2:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][C:6]=2[S:5][CH:4]=1)#[N:19]
Reactant: CCOC(=O)c1nc2scc(CBr)c2c(=O)[nH]1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2scc(CC#N)c2c(=O)[nH]1
Reaction time: 12 h
Yield: 18.1 %

Procedure:
To a mixture of ethyl 5-(bromomethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate (2000 mg, 6.31 mmol) in DMF (10 mL) was added sodium cyanide (649 mg, 13.2 mmol) at room temperature, and the mixture was stirred for 12 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as a pale-brown powder (300 mg, 18%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.Cl.[CH3:29][C:30]1([OH:34])[CH2:33][NH:32][CH2:31]1.Cl>O1CCCC1>[OH:34][C:30]1([CH3:29])[CH2:33][N:32]([S:2]([C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]3=[O:15])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:31]1
Reactant: CC1(O)CNC1
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CN(S(=O)(=O)c2ccc3c(C(=O)O)c[nH]c(=O)c3c2)C1

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g), diisopropylethylamine (3 ml) and 3-methylazetidin-3-ol hydrochloride (0.8 g) in tetrahydrofuran (8 ml) were heated at 55° C. for 3 days. The mixture was acidified with hydrochloric acid and then filtered to yield 7-[(3-hydroxy-3-methylazetidin-1-yl)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a pale pink solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Br:6][C:7](=[CH2:11])[C:8]([OH:10])=[O:9].B.O1CCCC1.O>O1CCCC1.C(Cl)(Cl)Cl>[Br:6][C:7]1([C:8]([OH:10])=[O:9])[CH2:11][CH:2]2[O:1][CH:5]1[CH:4]=[CH:3]2
Reactant: C=C(Br)C(=O)O
Reactant: c1ccoc1
Agent: B
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1(Br)CC2C=CC1O2
Temperature: 2 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
Distilled furan (6.8 g, 100 mmol) and 2-bromoacrylic acid (1.0 g, 6.6 mmol) were charged in a similar reactor as in Example 7, and the mixture was cooled to an inner temperature of 2° C. To this mixed solution was added dropwise a solution (0.7 ml, 0.7 mmol) of a borane-tetrahydrofuran complex (BH3.THF) in 0.93 M tetrahydrofuran over 5 min., while maintaining the inner temperature at not more than 2° C. After the completion of the dropwise addition, the mixture was stirred at the same temperature for 10 hr. Water (10 ml) and chloroform (10 ml) were added to the reaction mixture and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with chloroform (10 ml) and the extract was combined with the organic layer separated earlier. The mixture was dried over anhydrous sodium sulfate, concentrated and dried under reduced pressure for 2 hr. to give 2-bromo-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as a pale-yellow oily substance (1.3 g, main component:minor component=2:1, purity 77% (containing 23% of unreacted 2-bromoacrylic acid), yield 70% based on 2-bromoacrylic acid) being a mixture of an endo form and an exo form.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8]([Cl:11])=[N:9][CH:10]=1)=[O:4].[OH-].[Na+]>CO>[Cl:11][C:8]1[C:7]2[CH:12]=[CH:13][N:14]([CH3:15])[C:6]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=1
Reactant: COC(=O)c1cnc(Cl)c2ccn(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1ccc2c(Cl)ncc(C(=O)O)c21
Yield: 98.1 %

Procedure:
To a solution of 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid methyl ester (0.5 g), in methanol (20 ml) was added aqueous 2M sodium hydroxide solution (2 ml) and the mixture was heated to reflux for 4 hours. The methanol was evaporated and the residue was dissolved in water (50 ml) and acidified to pH 1 using aqueous 2M hydrochloric acid. Solid sodium chloride was added to saturated the aqueous phase, the solution was extracted with tetrahydrofuran (2×50 ml). The tetrahydrofuran layers were combined and evaporated to afford the title compound (460 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28](=[O:30])[CH3:29]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:27][C:28](=[O:30])[CH3:29])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: CC(=O)CCl
Reactant: Fc1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a stirred solution of 6-bromo-5-(2,4-difluorophenoxy)-1H-indazole (prepared according to Example 16, Steps A-D; 10.07 g, 31.0 mmol) in DMF (150 mL) at ambient temperature was added cesium carbonate (30.3 g, 92.9 mmol), followed by chloroacetone (5.2 mL, 65.1 mmol). The resulting mixture was vigorously stirred at ambient temperature for 1 hr, then diluted with water (1000 mL). After stirring for 1 hr, the precipitate that formed was collected by filtration, washed with water, and air-dried. This material was dissolved in boiling ethanol (150 mL), and then of water (80 mL) was added. The resulting mixture was cooled at 2° C. for 16 hr. The crystals that formed were collected by filtration, washed with 50/50 water/ethanol, and dried under vacuum to afford the title compound as a light orange powder (8.13 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[C:28]([Cl:44])[CH:27]=2)([CH3:25])[CH2:21][CH2:22][CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[N:45]1C2C(=CC=CC=2)C=CC=1COC1C=CC(C(C2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)(C)CCCO)=CC=1>>[Cl:44][C:28]1[CH:27]=[C:26]([C:20]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)=[C:2]([Cl:1])[CH:3]=2)([CH3:25])[CH2:21][CH2:22][CH2:23][O:24][NH2:45])[CH:31]=[CH:30][C:29]=1[O:32][CH2:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1
Reactant: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Product: CC(CCCON)(c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
The desired compound was prepared according to the method of Example 5, steps 1 and 2, except substituting 4,4-bis(3-chloro-4-(2-quinolylmethoxy)phenyl)pentan-1-ol, prepared as in step 1, for 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentan-1-ol.