Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.Br[C:38]1[CH:39]=[CH:40][C:41]([NH:49][C:50]2[CH:51]=[N:52][CH:53]=[N:54][CH:55]=2)=[C:42]([CH:48]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44].C(#N)C.C(=O)(O)[O-].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:38]3[CH:39]=[CH:40][C:41]([NH:49][C:50]4[CH:51]=[N:52][CH:53]=[N:54][CH:55]=4)=[C:42]([CH:48]=3)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH:16]=2)[N:11]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:10]=1
Reactant: CN(C)C(=O)c1cc(Br)ccc1Nc1cncnc1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(Nc4cncnc4)c(C(=O)N(C)C)c3)cc12
Yield: 50 %

Procedure:
125 mg (0.25 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 14 mg (17 μmol) of dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct and 65 mg (0.22 mmol) of 5-bromo-N,N-dimethyl-2-(pyrimidin-5-ylamino)-benzamide were place in a microwave vial. 1.5 mL of acetonitrile, 0.75 mL of tetrahydrofuran and 1.5 mL of a saturated aqueous solution of sodium bicarbonate were added. The vial was sealed and irradiated in a Personal Chemistry® Optimizer to 130° C. for 20 min. The organic layer was separated and evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate containing 10% v/v of methanol in hexanes to afford 67 mg (0.11 mmol, 50%) of 5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-(pyrimidin-5-ylamino)-benzamide. MS: m/z 619.0 (M+H+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([CH3:30])[C:9]3[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=3[CH:11]=[C:12]([CH2:13][C:14]([O:16]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:6]=2[CH:5]=1)[CH3:2].[CH3:33][NH:34][CH3:35].O>C(Cl)(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([CH3:30])[C:9]3[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=3[CH:11]=[C:12]([CH2:13][C:14](=[O:16])[N:34]([CH3:35])[CH3:33])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CNC
Reactant: CCSc1ccc2c(c1)C(CC(=O)Oc1ccc([N+](=O)[O-])cc1)=Cc1ccccc1N2C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCSc1ccc2c(c1)C(CC(=O)N(C)C)=Cc1ccccc1N2C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 11.35 g of 2-ethylthio-5-methyl-11-(p-nitrophenoxycarbonyl)methyl [5H] dibenzo (b,f) azepine in 45 ml of chloroform was stirred until dissolution occured and a solution of 12 ml of dimethylamine in 45 ml of chloroform was added dropwise thereto in 10 minutes. The mixture was stirred for 1 hour at room temperature and then was poured into 250 ml of ice and water. The organic phase was recovered by decanting and was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure to obtain 9 g of 2-ethylthio-5-methyl-11-dimethylcarbamoylmethyl [5H] dibenzo (b,f) azepine which was used as is for the next step. The product occured as a yellow oil soluble in chloroform, ethanol and ethyl acetate and insoluble in water.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:11][CH:10]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.C(N(CC)CC)C.Cl[C:37](=[O:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>ClCCl>[C:37]([N:8]([CH2:7][CH2:6][N:5]1[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]2[C:1]1=[O:28])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]([F:22])([F:21])[CH:18]([F:19])[F:20])=[CH:13][CH:14]=1)([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:43]
Reactant: O=C1c2ccccc2C(=O)N1CCNc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N(CCN1C(=O)c2ccccc2C1=O)c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To the mixture of the obtained N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (3.2 g), triethylamine (1.2 ml) and dichloromethane (60 ml), was added dropwise a solution of ethyl chloroglyoxylate (0.9 ml) in dichloromethane (10 ml) at -65° C. The reaction solution was stirred for 1 hour at -40° C., and then ice-water (50 ml) was added thereto to fractionate. The dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-ethoxalyl-N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (3.1 g) as colorless powdery crystals.
Reaction SMILES: C([N:8]1[CH2:31][CH:30]([C:32]2[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=2)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([N:13]2[CH2:14][CH2:15][C:10]3([O:29][CH:30]([C:32]4[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=4)[CH2:31][NH:8][CH2:9]3)[CH2:11][CH2:12]2)=[O:17])=[CH:19][C:20]=1[CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2nccn2C)O3)ccc1OC(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2CCC3(CC2)CNCC(c2nccn2C)O3)ccc1OC(C)C
Temperature: 65 °C
Yield: 92.1 %

Procedure:
To a solution of [8-benzyl-10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (50 mg, 0.10 mmol) in EtOH (500 μL) was added Pd(OH)2 (6.98 mg, 0.01 mmol) and ammonium formate (29 mg, 0.46 mmol) and the reaction mixture was heated at 65° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered and washed with sat. aq. NaHCO3 (pH 10)/brine. The aqueous was extracted further with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give (4-isopropoxy-3-methyl-phenyl)-[10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone (38 mg, 94%) as a clear colorless oil. ESI-MS m/z calc. 412.2. found 413.3 (M+1)+; Retention time: 1.16 minutes (3 min run).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[CH3:21])=[N:6][CH:7]=1.[C:22]1([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[NH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:22]1([C:28](=[N:29][C:2]2[N:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]3[CH3:21])=[N:6][CH:7]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1cnc(Br)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1cnc(N=C(c2ccccc2)c2ccccc2)cn1
Temperature: 96 °C
Yield: 98.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 230a (2.6 g, 7.3 mmol), diphenylmethanimine (1.3 g, 7.3 mmol), Pd2(dba)3 (669 mg, 0.73 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (968 mg, 1.46 mmol), Cs2CO3 (4.7 g, 14.6 mmol), and 1,4-dioxane (40 mL). After three cycles of vacuum/argon flush, the mixture was heated at 96° C. for 3 hrs. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 3:1) to afford 230b as red oil (3.3 g, 75%). MS: [M+H]+ 458.3.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.CCN(C(C)C)C(C)C.Cl[CH2:31][O:32][CH3:33].O>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH2:31][O:32][CH3:33])([CH3:18])[CH2:13]1
Reactant: COCCl
Reactant: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOCC1(C)CCCN(CC2COc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]methanol (0.20 g, 0.72 mmol) in dry DCM (10 ml) at 0° C. was added DIPEA (0.42 ml) and chloromethylmethyl ether (0.11 ml). The reaction mixture was stirred at RT for 16 h. Water was added and the product was extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[N:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: O=Cc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 80 °C
Yield: 55.5 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (1 g, 2.15 mmol) and (6-formylpyridin-3-yl) boronic acid (0.539 g, 2.31 mmol) in dioxane/water mixture (15 mL+3 mL), Na2CO3 (0.82 g, 7.74 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.288 g, 0.25 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 80° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the desired compound (0.60 g, 57%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].FC(F)(F)C(O)=O.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[CH3:68][C:69]([O:72][C:73]([N:75]1[CH2:80][CH2:79][CH2:78][CH2:77][C@H:76]1[C:81](O)=[O:82])=[O:74])([CH3:71])[CH3:70].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:81]([C@@H:76]2[CH2:77][CH2:78][CH2:79][CH2:80][N:75]2[C:73]([O:72][C:69]([CH3:71])([CH3:70])[CH3:68])=[O:74])=[O:82])=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), (2S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-piperidinecarboxylic acid (0.0236 g, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography with hexane:ethyl acetate to give the partially pure (˜85%) compound (0.028 g) as a clear resin.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]([C:18]([O:20]C)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:22])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].O.[Cl-].[NH4+]>C1COCC1>[CH2:1]([N:8]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:22])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1Cc2cc(F)ccc2CN1Cc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1Cc2cc(F)ccc2CN1Cc1ccccc1
Yield: 99.4 %

Procedure:
460 mg of methyl 2-benzyl-6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylate and 640 mg of lithium hydroxide.monohydrate were dissolved in 5 mL of THF:H2O=1:1, followed by stirring under reflux for 1 hour. Water was added to the reaction liquid, followed by neutralization by addition of ammonium chloride and an aqueous sodium bicarbonate solution and extraction with chloroform, and the organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 436 mg (yield 99%) of a title compound as a pale yellow oily substance.
Reaction SMILES: C1(CBr)CC1.CC1C=CC(S(O[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=O)=O)=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:34]2[CH2:38][CH2:37][NH:36][C:35]2=[O:39])[S:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH:18]1([CH2:17][N:36]2[CH2:37][CH2:38][N:34]([C:26]3[S:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:24]([CH3:23])[N:25]=3)[C:35]2=[O:39])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCCC3)C2=O)nc1C
Yield: 62 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with cyclopentylmethyl 4-methylbenzenesulfonate to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 62% yield: 1H NMR (300 MHZ, CDCl3) δ 4.20 (q, J=7.2 Hz, 2H), 4.04-3.99 (m, 2H), 3.52-3.41 (m, 2H), 3.17 (d, J=7.5 Hz, 2H), 2.46 (s, 3H), 2.16-1.08 (m, 12H); MS (ES+) m/z 338.3 (M+1).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:17](O)=O.C=O.[OH-].[Na+]>CCOC(C)=O>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1
Reactant: O=CO
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 120 °C
Yield: 70.1 %

Procedure:
To 4-(4′-nitrophenyl)piperazine hydrochloride (1.00 g, 4.10 mmol) was added formic acid (1.55 mL, 41.0 mmol) and 37% aq. formaldehyde (3.06 mL, 41.0 mmol) in a microwave vessel and the reaction was heated at 120° C. for 3 minutes. To the cooled reaction mixture was added EtOAc (100 mL) and 2 M aq. NaOH (70 mL). The layers were separated and the organic layer was washed with brine (50 mL), the layers were separated and the aqueous brine layer was extracted with EtOAc (50 mL), the organic layers were combined and dried (Na2SO4), filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-60% methanol (containing 1% ammonia solution) in EtOAc) to give the title compound (I11) (0.636 g, 70% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 8.07-8.01 (m, 2H), 7.05-6.99 (m, 2H), 3.48-3.40 (m, 4H), 2.46-2.39 (m, 4H), 2.21 (s, 3H). LCMS Method C: rt 1.45 min; m/z 222.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)OC)c1
Temperature: 60 °C

Procedure:
To 3.3 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 3.3 mmol potassium carbonate in 50 ml acetone was added dropwise 4.9 mmol 2,2,2-trifluoro-ethyl trifluoromethanesulfonate, and the mixture was heated at 60° C. for 16 h. The mixture was then concentrated in vacuo. The residue was suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo, and the residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 3:7) to afford the tide compound. MS (m/e): 328.0 (M+H+, 100%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][O:25][C:26](=[O:46])[C:27]([C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[F:45])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][O:25][C:26](=[O:46])[C:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:5]=[C:6]([O:8][CH3:9])[N:7]=2)[CH:33]=[CH:32][C:31]=1[F:45])([CH3:29])[CH3:28]
Reactant: COc1nc(Cl)cc(NCCc2ccc(OC(F)(F)F)cc2)n1
Reactant: COC(=O)C(C)(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(C)(C)c1cc(-c2cc(NCCc3ccc(OC(F)(F)F)cc3)nc(OC)n2)ccc1F
Yield: 30.2 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-trifluoromethoxyphenyl)-ethyl]amine (1.6 g), 2-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methyl-propionic acid methyl ester (0.63 g), Cs2CO3 (11.6 g) and tetrakis(triphenylphosphine)palladium (0) (33 mg) in water (8 mL) and DME (32 mL) is heated at 90° C. for 16 hours. The solution is poured into water and extracted with EtOAc (2×200 mL). The combined extract is dried over sodium sulfate, filtered, evaporated in vacuo and chromatographed on silica gel eluting with EtOAc to afford 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid methyl ester (300 mg). MS: 508 (M+H); 1H NMR (300 MHz, CD3OD), □7.8, (d, 1H, J=0.3 Hz); 7.7 (m, 1H); 7.4 (d, 2H, J=0.4 Hz); 7.2-7.3 (m, 4H); 6.6 (s, 1H); 4.2 (s, 3H); 4 (s, 3H); 3.9 (m, 2H); 3.05 (t, 2H); 1.65 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH2:22]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[CH2:22])=[CH:12][CH:11]=2)[N:8]=1
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a stirred suspension of 4-((6-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde (4 g, 14.97 mmol) and methyl(triphenyl)phosphonium bromide (5.35 g, 14.97 mmol) in dry THF (40 mL) was added NaH (2.096 g, 52.4 mmol) under nitrogen at 0° C. The mixture was stirred at room temperature for 2 h. The organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (2.4 g, 9.05 mmol, 60.4% yield) as a light green oil. LCMS: rt=3.80 min, [M+H+]=266
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH2:32][NH2:33])[CH:29]=[CH:28][C:27]=4[Cl:34])=[N:24][C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1.O>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH2:32][NH:33][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[O:6])[CH:29]=[CH:28][C:27]=4[Cl:34])=[N:24][C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Temperature: 25 °C

Procedure:
A solution of pivaloyl chloride (34 mg; 0.28 mmol) in DCM (1 mL) was added dropwise to a mixture of N-(4-bromo-phenyl)-2-(2-chloro-5-{[amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide ((see Example 72, step (d)) 150 mg; 0.27 mmol), TEA (41 mg; 0.41 mmol) and DCM (2 mL) at 0° C. The resulting mixture was stirred over night at rt, poured into water and extracted with DCM. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from EtOAc/petroleum ether to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:14])[NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:5].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>C(O)(=O)C.C(O)C>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[NH:1][CH:24]([C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=1)[N:6]([CH2:7][C:8]([NH:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:14])[C:4]2=[O:5]
Reactant: CC(C)(C)NC(=O)CNC(=O)c1cc(Br)ccc1N
Reactant: O=Cc1cccc(Cl)c1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)CN1C(=O)c2cc(Br)ccc2NC1c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
In a capped 20 mL scintillation vial, a solution of 2-amino-5-bromo-N-(tert-butylcarbamoylmethyl)benzamide (0.65 g, 2.0 mmol), 3-chlorobenzaldehyde (0.27 mL, 2.4 mmol) and catalytic glacial acetic acid (2 drops) in anhydrous ethanol (10 mL) was heated with stirring at 85° C. for 16 h. The resulting white suspension was cooled to room temperature, the white solid collected by suction filtration and washed with cold EtOH to give 2-[6-bromo-2-(3-chlorophenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-N-tert-butylacetamide (0.53 g, 1.21 mmol, 58%).