Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:55]CC=C)(=[O:54])[CH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([O:16][C@:17]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=1[F:53])([CH2:40][N:41]1[CH:45]=[N:44][CH:43]=[N:42]1)[C@H:18]([S:20][C@@H:21]1[CH2:26][O:25][C@@H:24](/[CH:27]=[CH:28]/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=2[F:39])[O:23][CH2:22]1)[CH3:19])=[O:15])=[O:5].O.C([SnH](CCCC)CCCC)CCC.CCCCCC>ClCCl.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>[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([O:16][C@:17]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=1[F:53])([CH2:40][N:41]1[CH:45]=[N:44][CH:43]=[N:42]1)[C@H:18]([S:20][C@@H:21]1[CH2:26][O:25][C@@H:24](/[CH:27]=[CH:28]/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=2[F:39])[O:23][CH2:22]1)[CH3:19])=[O:15])(=[O:5])[CH2:3][CH2:2][C:1]([OH:55])=[O:54]
Reactant: C=CCOC(=O)CCC(=O)OCc1ccccc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1ccccc1COC(=O)CCC(=O)O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
Allyl 2-[[(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propoxy]carbonyl]benzyl succinate (150 mg, 1.84×10-4 mol) obtained from Example 19-(2) and bis(triphenylphosphine)dichloropalladium (2 mg) were dissolved in dichloromethane (1.5 ml). To the mixture was added water (0.1 ml), and tributyltin hydride (80 mg, 2.7×10−4 mol) was slowly added thereto over a period of 5 minutes at room temperature. The resulting mixture was stirred at room temperature for 15 minutes further, and then hexane was added thereto. The liberated oily insoluble material was separated by removing the supernatant liquid slowly. The insoluble residue was further washed twice with hexane. The oily residue was subjected to chromatography on a silica gel (8 g) column (eluent; ethyl acetate), and then purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d.×600 mm) and JAIGEL-2H (20 mm i.d.×600 mm) connected in series for use; solvent, chloroform] to afford the title compound (123.9 mg, 87% yield) as a colorless amorphous solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([OH:19])[C:15]1=[O:20])=[O:13])C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([OH:19])[C:15]1=[O:20])=[O:13]
Reactant: COc1ccc(C(=O)N2CC[C@H](O)C2=O)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CC[C@H](O)C2=O)cc1O

Procedure:
2.40 g of (S)-1-(3-benzyloxy-4-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone are hydrogenated in 100 ml of tetrahydrofuran over 2.00 g of 5% palladium/carbon with hydrogen at atmospheric pressure. After removal of the catalyst by filtration, concentration of the filtrate and crystallization from ethyl acetate/diethyl ether, there is obtained (S)-1-(3-hydroxy-4-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone of melting point 131°-132°; [α]D20 =-180°; [α]54620 =-223°; [α]43620 =-464° (chloroform, c=1.0).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(C)cc1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4ccccc42)CN(C)CC3)cc1
Yield: 2.1 %

Procedure:
The title compound was prepared according to General Method 2. 2,3,4,5-tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (See Example 3) (200 mg, 1.07 mmol), 4-methylstyrene (1.41 mL, 10.7 mmol) and NaH (250 mg, 60% dispersion in oil, 6.25 mmol) in DMF (6 ml) at 200° C. for 16 h to obtain 7 mg of 2,3,4,5-tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=NC(C(=O)N(C)C)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[N:28]1([C:32]([C:34]2[N:39]=[CH:38][C:37](Br)=[CH:36][N:35]=2)=[O:33])[CH2:31][CH2:30][CH2:29]1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:37]2[CH:36]=[N:35][C:34]([C:32]([N:28]3[CH2:31][CH2:30][CH2:29]3)=[O:33])=[N:39][CH:38]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(c1ncc(Br)cn1)N1CCC1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)nc2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from azetidin-1-yl-(5-bromo-pyrimidin-2-yl)-methanone (172a) (331 mg, 1.37 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (304 mg, 1.37 mmol) to give a white foam (136 mg, 36% yield). 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1 H) 8.53 (s, 2 H) 7.29 (s, 1 H) 4.64 (t, J=7.45 Hz, 2 H) 4.30 (t, J=7.58 Hz, 2 H) 3.88 (s, 3 H) 2.93 (s, 2 H) 2.36 (t, J=7.45 Hz, 2 H) 1.50 (s, 6 H); LCMS for C20H21N3O5 m/z 384.00 (M+H+).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.C1C=CC2N(O)N=NC=2C=1.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>ClCCl>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:38]=[CH:37][C:33]([C:34]([N:61]5[CH2:66][CH2:65][O:64][CH2:63][CH2:62]5)=[O:36])=[CH:32][C:31]=4[F:39])[C:17]=3[N:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:20]=2)=[CH:13][N:14]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(C(=O)N3CCOCC3)cc2F)cn1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (120 mg, 0.177 mmol) obtained in Step A in 1-D-21, WSCI (68 mg, 0.35 mmol), HOBt (24 mg, 0.15 mmol) and morpholine (31 μl, 0.35 mmol), dichloromethane (4 ml) was added, followed by stirring for 1 hour. The reaction mixture was washed with water, and subsequently dried over sodium sulfate. The drying agent was removed, followed by concentration and drying. To this, TFA (2 ml) was added, followed by stirring at 80° C. for 4 hours. After TFA was removed under reduced pressure, dichloromethane was added, followed by washing with aqueous sodium hydrogencarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated, to obtain a crude product. Purification by silica gel column chromatography (dichloromethane/methanol=10/1) afforded {4-[4-(2-amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-phenyl}-morpholin-4-yl-methanone as a colorless solid (86 mg, 96%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH2:12][O:13][CH3:14])=[CH2:2].B.[O:16]1CCCC1.[OH-].[Na+].OO>O1CCCC1>[OH:16][CH2:2][CH2:1][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: C1CCOC1
Reactant: C=Cc1cc(OC)ccc1OCOC
Agent: B
Agent: OO
Agent: [Na+]
Product: COCOc1ccc(OC)cc1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 33.8 g (0.174 moles) of 2-ethenyl-4-methoxy-1-O-methoxymethylphenol in 300 ml of dry tetrahydrofuran at 0° was added 120 ml of a 1.0M borane-tetrahydrofuran solution. The solution was stirred at room temperature for 60 minutes, cooled to 0° and 48 ml of 10% NaOH was added dropwise. Then 41 ml of 30% H2O2 was added with caution and the mixture was stirred at room temperature for 30 minutes. The solution was partitioned between ether and water and the ether layer was washed with aqueous NaHCO3 and brine, dried (Na2SO4) and evaporated. The oily residue was purified by Prep. 500 HPLC using 40% ethylacetatehexane to afford 27.3 g (73%) of 2-(2-hydroxyethyl)-4-methoxy-1-O-methoxymethylphenol as a colorless liquid. NMR (CDCl3) δ2.15 (s, br, 1H, --OH), 2.8 (t, 2 H, J=7 Hz), 3.40 (s, 3H), 3.65 (s, 3H), 3.73 (m, 2H), 5.05 (s, 2H), 6.55 (d of d, 1H), 6.61 (s, 1H), 6.88 (d, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:48])[N:4]([CH3:47])[C:5](=[O:46])[C:6]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[NH:29][C:30]2[C:35]([C:36]=1[C:37]1[C:38](=[O:45])[N:39]([CH3:44])[C:40](=[O:43])[C:41]=1Br)=[CH:34][CH:33]=[CH:32][CH:31]=2.CN(C=O)C.[NH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CCN(CC)CC>[CH3:47][N:4]1[C:5](=[O:46])[C:6]2[C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[NH:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=4[C:36]=3[C:37]3[C:38](=[O:45])[N:39]([CH3:44])[C:40](=[O:43])[C:41]=3[N:57]3[CH2:58][CH2:59][N:54]([CH2:55][CH2:56]3)[C:2]=2[C:3]1=[O:48]
Reactant: CN1C(=O)C(Br)=C(c2c(CCCCCCCCCCCCc3[nH]c4ccccc4c3C3=C(Br)C(=O)N(C)C3=O)[nH]c3ccccc23)C1=O
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)C2=C(C1=O)N1CCN(CC1)C1=C(C(=O)N(C)C1=O)c1c([nH]c3ccccc13)CCCCCCCCCCCCc1[nH]c3ccccc3c12
Temperature: 80 °C
Reaction time: 48 h

Procedure:
0.75 mmol of 3-bromo-4-(2-(12-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)dodecyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione is dissolved in 200 ml of absol. DMF, treated with 0.5 ml of abs. NEt3 and heated to 80° C. The solution of 0.75 mmol of piperazine in 100 ml of absol. DMF and 0.5 ml of NEt3 is then slowly added dropwise to the warm solution and the mixture is then stirred at 80° C. for 48 h. The solvent is then removed in vacuo to the greatest possible extent and the residue is treated with 100 ml of 1N HCl. This solution is then extracted with ethyl acetate (in total about 600 ml), the combined extracts are dried over Na2SO4 and the solvent is stripped off in vacuo. Purification is carried out by column chromatography (SiO2, CH2Cl2/EA9.5:0.5) orange crystals, yield: 0.267 g (52%).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:14][CH2:13][CH2:12][CH2:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ICCCc1ccccc1
Reactant: Cc1ncccc1C(=O)O
Product: O=C(O)c1cccnc1CCCCc1ccccc1
Yield: 75.3 %

Procedure:
Starting from 2.1 g (15.0 mmol) of 2-methyl-nicotinic acid and 5.5 g (22.5 mmol) of 1-iodo-3-phenyl-propane, 2.9 g (11.3 mmol, 75%) of 2-(4-phenylbutyl)nicotinic acid were obtained according to the process described in precursor VB006.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:13][C:12]([C:31]2[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:32]=[C:33]([Cl:39])[C:34]([OH:38])=[C:35]([Cl:37])[CH:36]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino]cyclohexylcarbamate (25.7 mg, 0.045 mmol) was reacted with TFA (2 mL) to afford the desired product (8.8 mg, 42%) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.35 (d, J=1.7 Hz, 1H), 8.04 (dd, J=8.7, 1.9 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.69 (s, 2H), 4.14 (s, 1H), 3.29-3.20 (m, 1H), 2.88-2.79 (m, 1H), 2.37 (d, J=12.5 Hz, 2H), 2.19 (d, J=11.0 Hz, 2H), 1.76-1.64 (m, 2H), 1.64-1.52 (m, 2H), 1.23-1.18 (m, 2H), 1.15-1.10 (m, 2H); ESI MS m/z 470 [C25H25Cl2N3O2+H]+; HPLC 94.9% (AUC), tR=10.74 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=1)[CH3:2].C(N(C(C)C)CC)(C)C.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)c(CNCc2ccccc2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Temperature: 25 °C

Procedure:
3-(Benzylamino-methyl)-4-bromo-benzoic acid ethyl ester (5.0 g, 12.9 mmol) and diisopropylethylamine (6.7 mL, 38.7 mmol) were combined in CH2Cl2 (100 mL) at room temperature. Cyclopropanecarbonyl chloride (1.77 mL, 19.4 mmol) was added dropwise, and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was worked-up and purified by silica gel chromatography to give 3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzoic acid ethyl ester.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:39][CH2:40][OH:41]>O1CCCC1>[OH:41][CH2:40][CH2:39][N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:22]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:23])[CH2:26][CH2:27]1
Reactant: OCCBr
Reactant: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCN(CCO)CC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 43 %

Procedure:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea (0.05 g, 0.12 mmol), triethylamine (0.02 mL, 0.15 mmol) and 2-bromoethanol (0.019 mL, 0.15 mmol) were dissolved in tetrahydrofuran (3 mL) and stirred at 60° C. for 7 h. The reaction mixture was evaporated. The residue was subjected to column chromatography (basic silica gel, methylene chloride/methanol 19:1, 9:1) to yield the title compound (0.023 g, 41%) as a white solid; MS: m/e=446.8 (M+H+).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:12]1([CH3:35])[CH:17]=[CH:16][C:15]([S:18](OCC2C([N+]([O-])=O)=CC=CC=2[N+]([O-])=O)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C1(S(C(S(C2CCCCC2)(=O)=O)=[N+]=[N-])(=O)=O)CCCCC1>>[CH3:3][C:2]([S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:35])=[CH:13][CH:14]=1)(=[O:20])=[O:19])([CH3:4])[C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)C(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCc2c([N+](=O)[O-])cccc2[N+](=O)[O-])cc1
Agent: [N-]=[N+]=C(S(=O)(=O)C1CCCCC1)S(=O)(=O)C1CCCCC1
Product: Cc1ccc(S(=O)(=O)C(C)(C)C(=O)c2ccccc2)cc1

Procedure:
Using isobutyrophenone, the reaction was carried out in the same manner as described in Synthesis Example 9, (2) and (3), the crude solid was recrystallized from methanol to afford 2-methyl-2-(p-toluenesulfonyl)propiophenone as a white needles.
Reaction SMILES: N([O-])=[O:2].[Na+].[Cl:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:7]=1[C:8](N)=[O:9]>O.OS(O)(=O)=O>[Cl:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:7]=1[C:8]([OH:2])=[O:9]
Reactant: NC(=O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
A solution of NaNO2 (9.59 g, 139 mmol) in water (95 mL) was added slowly to a solution of commercially available (Oakwood) 2,6-dichloro-4-(trifluoromethyl)nicotinamide (20.0 g, 77 mmol) in conc. H2SO4 resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60° C. for 18 h. The solution was cooled to 0° C. and then water (15 mL) was added. The resulting mixture was extracted with Et2O (3×) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated with hexanes and vacuum-filtered to afford 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (19 g, 95%) as an off-white solid: Rf=0.30 (9:1 CH2Cl2:MeOH), 1H-NMR (d6-DMSO, 300 MHz) 8 8.18 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1C(O)=O.C([N:17](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CC(O)(C)C.Cl[Cu]>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[NH2:17]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1F
Reactant: CCN(CC)CC
Agent: Cl[Cu]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Nc1ccc(C(F)(F)F)cc1F
Temperature: 50 °C
Yield: 57.9 %

Procedure:
To the solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (1 kg, 4.805 mol, 1.00 equivalent “eq.”) and CuCl (14.26 g, 0.144 mol, 0.03 eq.) in t-BuOH (11.7 L) was added triethylamine (TEA, 533.8 g, 5.286 mol, 1.10 eq.) dropwise at room temperature (rt). Then the solution was heated to 50° C. and diphenylphosphoryl azide (DPPA, 1393 g, 5.045 mol, 1.05 eq.) was added dropwise to the solution at 50-60° C. After heating at 80˜85° C. overnight the solution was concentrated under vacuum. The residual was dissolved in H2O and filtered. The filtrate was extracted with ethyl acetate. The organic layers was dried with Na2SO4, filtered and concentrated under vacuum. The residual was dissolved in tert-Butyl methyl ether (TBME) and HCl (gas) was bubbled in for 2 hours. The filtrate was collected and dissolved in water and basified with 2 M NaOH. The solution was extracted with TBME. The organic layers were dried and concentrated under vacuum to give 2-fluoro-4-(trifluoromethyl) aniline (498 g, 58%) as a red oil.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][C:13]([OH:15])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([C:20]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:23][C:21]=1[NH2:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[CH:23][C:21]=1[NH:22][C:13](=[O:15])[CH2:12][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(CCC(CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1N
Reactant: O=C(O)CC1(c2ccccc2)CCCC1
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1NC(=O)CC1(c2ccccc2)CCCC1

Procedure:
Following a procedure similar to that described in Example 21, but using 2-(1-phenylcyclopentyl)acetic acid [prepared as described in Preparation 21] and 2-t-butyl-5-[4-cyclohexyl-3-(t-butyldimethylsilyloxy)butyl]aniline [prepared by a procedure similar to that described in Preparation 11(i)] as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[CH:8]=[N:7][CH:6]=1.[CH3:17][N:18](C=O)C>C(Cl)(Cl)Cl.[C-]#N.[C-]#N.[Zn+2].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].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]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]#[N:18])[CH:13]=2)[CH:8]=[N:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1cncc2ccc(Br)cc12
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cncc2ccc(C#N)cc12
Temperature: 120 °C
Reaction time: 22 h

Procedure:
A solution of (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (52 mg, 0.19 mmol), prepared as described as an intermediate for Intermediate 31, in DMF (3 ml) is added to zinc dicyanide (26 mg, 0.22 mmol) under a nitrogen atmosphere. To the resulting mixture is added 1,1′-bis(diphenylphosphino)ferrocene (15 mg) and tris(dibenzylideneacetone)dipalladium(0) (8 mg) and the resulting mixture stirred at 120° C. for 22 h. The solution is cooled and diluted with chloroform (30 ml) and washed with water (2×20 ml) followed by brine (20 ml). Further chloroform is added (40 ml) and the solution dried over MgSO4, filtered and concentrated. Repetitive flash silica column chromatography (eluants 40:1 CH2Cl2:methanol, then 50:1 CH2Cl2:methanol) gives (6-cyano-isoquinolin-4-yl)-acetic acid methyl ester [MH]+ 227. This intermediate is saponified by treatment with LiOH in 3:1 THF/water. The resulting mixture is partially evaporated to remove the THF, diluted to 10 ml with water then washed with ethyl acetate. The aqeous phase is then neutralised with 1M hydrochloric acid (to pH 4-5) and exhaustively extracted with ethylacetate. The organic phase is dried over MgSO4, filtered and concentrated to give (6-cyano-isoquinolin-4-yl)-acetic acid M+ 212.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[O:12]=[C:13]1[CH2:17][S:16][CH2:15][NH:14]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:14]2[C:13](=[O:12])[CH2:17][S:16][CH2:15]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C1CSCN1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CSCC2=O)cc1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 4-methoxybenzoyl chloride (20.7 g) in tetrahydrofuran (50 ml) was added dropwise to a mixture of 4-oxo-thiazolidine (12.5 g) and triethylamine (16.9 ml) in tetrahydrofuran (200 ml) at -5° C. with stirring. The mixture was stirred at that temperature for 3 hours and at room temperature for 4 hours, and allowed to stand overnight. After the solvent was evaporated in vacuo, the residue was mixed with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then with water, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(4-methoxybenzoyl)-4-oxothiazolidine (18.1 g) as slightly brown prisms.