Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:23]=1[CH3:39].Cl.O1CCOCC1.CN1C(=O)CCC1>>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:20][C:10]3[C:11]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:12][CH:13]=[C:8]([N:6]4[CH2:5][CH2:4][O:3][C@@H:2]([CH3:1])[CH2:7]4)[CH:9]=3)=[C:23]([CH3:39])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: C[C@H]1CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCO[C@@H](C)C2)cnc1N1CCOCC1
Temperature: 165 °C

Procedure:
Prepared according to Procedure K, method 2 using (S)-5-(2-methylmorpholino)-2-morpholinopyridin-3-amine (85 mg, 0.305 mmol; described herein), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (83 mg, 0.305 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (80 μL, 0.31 mmol), and NMP (350 μL, 3.7 mmol), and heating in a microwave at 165° C. for 3 h. Purification afforded 7-fluoro-3-methyl-N-(5-((2S)-2-methyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine as a yellow solid (absolute configuration of stereocenter not determined) 1H NMR (500 MHz, chloroform-d) δ ppm 8.70-8.76 (1H, m), 7.85-7.94 (2H, m), 7.75-7.85 (2H, m), 7.59 (1H, d, J=2.7 Hz), 7.39 (1H, ddd, J=7.1, 5.0, 1.6 Hz), 7.25-7.33 (1H, m), 6.77 (1H, s), 6.23 (1H, d, J=2.7 Hz), 3.84-3.99 (5H, m), 3.56-3.71 (2H, m), 3.23 (4H, br. s.), 3.15 (1H, dt, J=11.7, 2.2 Hz), 3.02-3.11 (1H, m), 2.63-2.74 (1H, m), 2.31-2.43 (4H, m), 1.16 (3H, d, J=6.4 Hz). Mass Spectrum (ESI) m/e=515.2 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1C(C)(C)CCCC1(C)C.[C:31]1([C:37]#[CH:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:41]>CN(C)C1C=CN=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[C:31]1([C:37]#[C:38][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C#Cc1ccccc1
Reactant: CCCCOC(=O)Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCOC(=O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
0.25 g (1.1 mmol) of palladium(II) acetate and 1.16 g (4.4 mmol) of triphenylphosphine are introduced into 100 ml of dichloromethane in a 250 ml round-bottomed flask under argon. The yellow solution is stirred at room temperature for 1 h. Then 0.06 g (0.5 mmol) of 4-dimethylaminopyridine, 8.53 g (55.5 mmol) of 1,2,2,6,6-pentamethylpiperidine and 5.1 g (50 mmol) of phenylacetylene are added. The mixture is heated to reflux at 40° C. and then 6.83 g (50 mmol) of n-butyl chloroformate are added dropwise over the course of 1 h. After a reaction time of 20 h, the reaction mixture is worked up by distillation to isolate n-butyl phenylpropynoate in 85% yield.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([NH2:33])=[N:11][C:12]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)=[N:13][C:14]=1[NH2:15])(C(C)(C)C)(C)C.Cl>O1CCCC1>[NH2:33][C:10]1[C:9]([OH:8])=[C:14]([NH2:15])[N:13]=[C:12]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:11]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: Cl
Solvent: C1CCOC1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1O
Yield: 47.1 %

Procedure:
447 mg (0.96 mmol) of the compound obtained in example 57A were initially charged in 10 ml of tetrahydrofuran, and 6 ml of 3M hydrochloric acid were added. The next day, the mixture was concentrated to dryness and the residue was stirred with acetonitrile, water and dimethylformamide The precipitate was filtered off and washed with acetonitrile. 159 mg of the title compound were obtained (92% purity; 43% of theory).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]1([N:25]2[C:29](=[S:30])[N:28]=[N:27][NH:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]([OH:42])[CH2:39][CH2:40]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]([OH:42])[CH2:39][CH2:40][S:30][C:29]1[N:25]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:26]=[N:27][N:28]=1
Reactant: OCCC(O)c1ccccc1Cl
Reactant: S=c1nn[nH]n1-c1cccc2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OC(CCSc1nnnn1-c1cccc2ccccc12)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
DIAD (82 μL, 0.42 mmol) was added dropwise to a solution of 1,2-dihydro-1-(1-naphthalenyl)-5H-tetrazole-5-thione (80.0 mg, 0.35 mmol), 1-(2-chlorophenyl)-1,3-propanediol (65.4 mg, 0.35 mmol), and PPh3 (110 mg, 0.42 mmol) in THF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h then was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:(CH3)2CO, 95:5) to give the title compound (70 mg, 50% yield) as a white solid.
Reaction SMILES: C(OC([N:8]([C:19]1[CH:24]=[C:23]([N:25](C(OC(C)(C)C)=O)[C:26]([NH2:35])=[N:27]C(OC(C)(C)C)=O)[CH:22]=[C:21]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][N:44]=2)[C:20]=1[CH3:51])[C:9]([NH2:18])=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:52]>ClCCl.O1CCOCC1>[ClH:52].[ClH:52].[ClH:52].[NH:8]([C:19]1[CH:24]=[C:23]([NH:25][C:26]([NH2:35])=[NH:27])[CH:22]=[C:21]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][N:44]=2)[C:20]=1[CH3:51])[C:9]([NH2:18])=[NH:10]
Reactant: COc1ccnc(-c2cc(N(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)cc(N(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)c2C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccnc(-c2cc(NC(=N)N)cc(NC(=N)N)c2C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2,4-bis(N,N′-bis(tert-butoxycarbonyl)guanidino)-6-(4-methoxypyridin-2-yl)toluene (0.15 g) in dichloromethane (3 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 3 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (50 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 2,4-diguanidino-6-(4-methoxypyridin-2-yl)toluene trihydrochloride (85 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].Br[CH2:13][C:14]#[N:15]>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:13][C:14]#[N:15])[CH2:10][CH2:11]1)[CH3:2]
Reactant: N#CCBr
Reactant: CCOCCN1CCNCC1
Product: CCOCCN1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 4-(2-Ethoxy-ethyl)-piperazine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=198.2; 1HNMR(DMSO-d6) 3.70 (s, 2H), 3.45 (q, 2H), 3.40 (q, 2H), 2.40-2.30 (m, 10H), 1.05 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][CH2:28][N:29]2[CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=[N:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][CH2:27][C:26]4[CH:43]=[CH:44][C:23]([F:22])=[CH:24][CH:25]=4)[CH:33]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cnn(CCc3ccc(F)cc3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccc(F)cc4)c3)c3cc(Br)cnc32)cc1
Yield: 30.97 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (200 mg, 0.41 mmol) was coupled with 1-(4-fluorophenethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 64C) (172 mg, 0.54 mmol) using sodium carbonate (130 mg, 1.23 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.020 mmol) in toluene/ethanol/water (20/10/5 ml) to afford 70 mg (30.97% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent. MS: m/z=540.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][C:30]=1[C:40]([F:43])([F:42])[F:41]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][C:30]=2[C:40]([F:41])([F:43])[F:42])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(1.29 g, 5.78 mmol) in THF (30 ml) was added 1.0M lithium bis(trimethylsilyl)amide in THF (5.66 ml, 5.66 mmol) at ambient temperature under nitrogen. The solution was stirred at ambient temperature for 30 min. To the solution was added a solution of ethyl 4-(bromomethyl)-3-(trifluoromethyl)benzoate (for a preparation see Intermediate 20)(1.6 g, 5.14 mmol) in THF (20 ml). The mixture was stirred for 3.5 h at ambient temperature under nitrogen. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (75 ml). The phases were separated and the aqueous phase washed with ethyl acetate (25 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave a pale yellow oil (2.8 g). The residue was loaded in dichloromethane and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.68 g); LCMS: (System 4) MH+=454, tRET=3.15 min.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]([OH:37])=O)[CH:24]=[C:23]1[CH2:38][CH2:39][N+:40]([O-:42])=[O:41])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[N:47]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C@H:25]([C:35](=[O:37])[NH2:47])[CH:24]=[C:23]1[CH2:38][CH2:39][N+:40]([O-:42])=[O:41])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1C(N)=O

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-(2-nitroethyl)-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 222, 4.0 g, 6.59 mmol) according to the procedure described for Intermediate 20. The desired product was obtained as an off-white foam (2 g, 50%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>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>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1I
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Product: FC(F)(F)c1ccccc1CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reaction time: 24 h
Yield: 29.7 %

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (6.0 g, 20.52 mmol) and 9-borabicyclo[3.3.1]nonane (164.1 ml, 82.07 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hrs, add 1-iodo-2-trifluoromethyl-benzene (8.37 g, 30.78 mmol), triphenylphosphine (861.0 mg, 3.28 mmol), tetrakis(triphenylphosphine)palladium(0)(474.1 mg, 0.41 mmol), and 3N NaOH (16.8 ml) and stir at 60°. After 22 hrs, remove the THF under vacuum and dissolve the residue in ethyl acetate. Wash the organic layer with 1N NaOH then combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue using ethyl acetate/hexanes (5:95) and reduce the appropriate fractions to residue. Stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H2SO4 then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Recrystallize the residue in warm ethanol to give 2.67 g (30%) of the title compound: mass spectrum (ion spray): mp 77°–82°; m/z=439.2 (M+1); Analysis for C27H29F3N2: calcd: C, 73.95; H, 6.67; N, 6.39; found: C, 74.11; H, 6.68; N, 6.50.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)([Cl:17])=O.C1(C)C=CC=CC=1>C1COCC1>[Cl:17][C:6]([OH:5])=[O:7].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Agent: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (201 mg, 1.0 mmol) in THF (2 mL) was added a 20% solution of phosgene in toluene (358 μL, 1.7 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Brc1ccccc1OCc1ccccc1
Temperature: 5 °C
Yield: 84.7 %

Procedure:
A mixture of 42 g (242 mmol) 2-bromophenol, 100 g (726 mmol) potassium carbonate and 45.6 g (266.4 mmol) benzyl bromide in 500 mL absolute ethanol was heated to reflux for 18 h. The reaction mixture was cooled to 5° C. in an ice/water bath and filtered. The filtered solid was washed with 200 mL dichloromethane. The filtrate was concentrated and the residue purified over silica eluting with hexanes to give 54 g (205 mmol, 85%) of 1-bromo-2-benzyloxy-benzene as a colorless oil. 1H NMR (400 MHz) CDCl3 7.54-7.56 (d, 1H), 7.46-7.48 (d, 2H), 7.28-7.40 (m, 3H), 6.90-6.93 (d,1H), 6.81-6.85 (t, 1H), 5.14 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH3:3].[H][H].Cl>[C].[Pd].C(O)(=O)C>[CH3:3][CH:2]([CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)C(CCC(=O)O)C(=O)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)C(CCC(=O)O)Cc1ccccc1
Yield: 86.7 %

Procedure:
4-(2-Propyl)-5-oxo-5-phenylpentanoic acid (5.50 g, 23.5 mmol) was subjected to hydrogen catalytic reduction at room temperature by the use of 10% palladium-carbon (0.6 g) as catalyst in a mixed solvent of acetic acid (60 ml) and 35% hydrochloric acid (3 ml). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 4.49 g of 4-(2-propyl)-5-phenylpentanoic acid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH2:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1.CC(C)([O-])C.[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd]>[NH2:16][CH:17]1[CH2:21][CH2:20][N:19]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=2)[CH2:18]1
Reactant: NC1CCNC1
Reactant: CN(C)CCn1ccc2ccc(Br)cc21
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CN(C)CCn1ccc2ccc(N3CCC(N)C3)cc21
Temperature: 120 °C

Procedure:
To a mixture of the 6-bromo-1-((N,N-dimethylamino)ethyl)-1H-indole (54 mg, 0.2 mmol), 3-aminopyrrolidine (6 equiv.) and sodium t-butoxide (1.4 equiv.) in xylene was added palladium acetate and P(t-Bu)3 (P/Pd=4). The mixture was heated at 120° C. overnight. The reaction was then poured into ice-cold water followed by extraction with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, and dried over Na2SO4 (anhydrous). The organic layer was concentrated in vacuo and purified by flash column chromatography yielding 6-[3-Aminopyrrolidin-1-yl]-1-((N,N-dimethylamino)ethyl)-1H-indole: (43 mg of a yellow oil, 80%).
Reaction SMILES: F[C:2](OB([O-])[O-])=[C:3]([F:5])[F:4].[K+].[K+].Br[C:13]1[S:17][C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:27])[C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[N:15][C:14]=1[CH:28](F)F.[B-](F)(F)(F)C=C.[K+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C.C(N(CC)CC)C.C(O)C>[F:4][CH:3]([F:5])[C:2]1[N:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:27])[C:22]=2[C:23]([O:25][CH3:26])=[O:24])[S:17][C:13]=1[CH:14]=[CH2:28]
Reactant: COC(=O)c1c(-c2nc(C(F)F)c(Br)s2)cnn1C
Reactant: [O-]B([O-])OC(F)=C(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=C[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1sc(-c2cnn(C)c2C(=O)OC)nc1C(F)F
Temperature: 100 °C
Reaction time: 17 h
Yield: 58 %

Procedure:
Potassium trifluorovinylborate (172 mg), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (31 mg), and triethylamine (59.4 μl) were added to an ethanol (2.1 ml) solution of the methyl 4-(5-bromo-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (150 mg) obtained in (Example 1.4) <Step 1>, and the obtained mixture was then stirred in a nitrogen atmosphere at 100° C. for 17 hours. Thereafter, potassium trifluoro(vinyl)borate (342 mg), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (62 mg), and triethylamine (59.4 μl) were added to the reaction solution, and the obtained mixture was stirred again in a nitrogen atmosphere at 100° C. for 2 hours 40 minutes. Thereafter, ethyl acetate (100 ml) and a saturated saline (50 ml) were added to the reaction solution. An organic layer was extracted, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=95:5-50:50), so as to obtain the title compound (74 mg) in the form of a colorless solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)s1
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: [K+]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 95 °C
Yield: 62.9 %

Procedure:
A mixture of 5-bromothiophene-2-carboxaldehyde 60.1 (1.03 g, 5.4 mmol), 4-(trifluoromethyl)benzeneboronic acid 61.1 (2.05 g, 10.9 mmol), K2CO3 (2.24 g, 16.2 mmol), and Pd(PPh3)4 (0.60 g, 0.54 mmol) in toluene (15 mL) was stirred for 5 Hours at 95° C. The mixture was cooled to room temperature, filtered through a pad of silica gel (EtOAc), and concentrated. The crude product was chromatographed on silica gel (0-30% EtOAc/hexane) to afford 61.2 (0.87 g, 63%) as off-white crystals. 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.78 (m, 3H), 7.70 (d, 2H), 7.48 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([NH:15][O:16][CH3:17])=[O:14].[C:22]([O-])(O)=[O:23].[Na+].ClC(OCC)=O.[H-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:11]2[C:12](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13](=[O:14])[N:15]([O:16][CH3:17])[C:22]1=[O:23]
Reactant: O=C([O-])O
Reactant: CONC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COn1c(=O)c2ccccc2n(-c2c(Cl)ccc(C)c2Cl)c1=O
Reaction time: 8 h
Yield: 52 %

Procedure:
2-(2,6-Dichloro-3-methYlphenyl)amino-N-methoxybenzamide (1.6 %) is added to a THF (20 ml) solution of NaHCO3 (0.14 g) and ethyl chloroformate (0.25 g) at -30° C. under argon. The reaction is allowed to stir overnight. The THF is evaporated and the residue is partitioned between diethyl ether and water. The organic layer is washed twice with water and brine after being dried over magnesium sulfate. The organic layer is concentrated to give a white solid, which is dissolved in THF and treated with sodium hydride at reflux for one hour under argon. The reaction is acidified with 1 N HCl and partitioned between ethyl acetate and water. The organic layer is washed with brine and dried (MgSO4). The solvent is evaporated and the residue is adsorbed onto a silica gel pad. The pad is washed with chloroform to give the product. Recrystallization from CH2Cl2 /Et2O gives 0.64 g (52% yield) of 1-(2,6-dichloro-3-methylphenyl)-3-methoxy-2,4-(1H,3H)-quinazolinedione, mp 211°-213° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:33]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:41][S:38]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)(=[O:40])=[O:39])=[O:31])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1cccnc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccnc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and pyridine-3-sulfonamide: 1H-NMR [CDCl3/CD3OD(10:1)] δ 9.10 (1H, d, J=2.2 Hz), 8.71-8.70 (1H, m), 8.24 (1H, d, J=8.3 Hz), 7.45-7.16 (1H, m), 6.26 (1H, br.s), 3.42-3.33 (2H, m), 2.80-2.73 (2H, m), 2.29 (3H, s), 2.20 (3H, s).