Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-])=O)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([NH2:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(N)cc(C(F)(F)F)c2)CC1
Yield: 88.7 %

Procedure:
Hydrogentate 4-(3-nitro-5-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (4.8 g, 11.9 mmol) in MeOH (120 mL) with 10% Pd on activated carbon (400 mg) at room temperature for 3 hours. Filter and concentrate into a white solid as the title compound (3.94 g, 10.55 mmol, 89%). MS (ES), m/z 372 (M−1). Use in the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)=O)([O-:3])=[O:2].C([BH3-])#N.[Na+]>[I-].[Zn+2].[I-].ClCCCl>[CH3:14][N:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH2:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1cccc1Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A mixture of 2-(3-nitrobenzoyl)-1-methylpyrrole (5.0 g, 21.7 mmol) [prepared as in Example 8, Step (a)], zinc iodide (10.38 g, 32.5 mmol), sodium cyanoborohydride (10.22 g, 162.7 mmol), and 1,2-dichloroethane (300 ml) was refluxed for 16 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and then concentrated to dryness. Purification of the residue on a Florisil® column (hexane-acetone, 98:1) gave 3-(1-methylpyrrol-2-ylmethyl) nitrobenzene (3.55 g, 75%) as a solid. ##STR43##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: O=C(CCl)N1CCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)C)c1
Yield: 11.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-piperidin-1-ylethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.9 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccccc1CBr
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CSc1ccc(Cl)cc1N
Yield: 85.8 %

Procedure:
Following General Procedure A, the title compound (1.6 g, 84%) was prepared from 2-amino-4-chlorobenzenethiol (969 mg, 6.06 mmol), methyl 2-(bromomethyl)benzoate (1.4 g, 6.11 mmol) and K2CO3 (4.2 g, 30.55 mmol) in DMF (50 ml).
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:20])[CH2:6][CH2:7][C@@:8]2([CH3:19])[C:17]=1[CH2:16][CH2:15][C:14]1[C:9]2=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][C:4]1[C:5](=[O:20])[CH2:6][CH2:7][C@@:8]2([CH3:19])[C:17]=1[CH2:16][CH2:15][C:14]1[C:9]2=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=1
Reactant: C[C@]12CCC(=O)C(N=[N+]=[N-])=C1CCc1cc(Cl)ccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)C(N)=C1CCc1cc(Cl)ccc12
Yield: 22 %

Procedure:
To a solution of (R) -1-azido-7-chloro-4,4a, 9,10-tetrahydro-4a-methyl-2 (3H) -phenanthreneone (0.210 g, 0.730 mmol) in tetrahydrofuran (8 mL) and water (1 mL) was added triphenylphosphine (0.325 g, 1.24 mmol). After refluxing for 20 minutes the mixture was cooled and the tetrahydrofuran evaporated. The resulting system was diluted with toluene (8 mL) and refluxed for 16 hours. The mixture was evaporated and the residue was purified by chromatography (Chromatotron, Harrison Research, Palo Alto, Calif.) (15% ethyl acetate/hexane) twice to give 42 mg (22%) of the title amine as a white powder. IR (KBr) 1648 (CO)cm-1 ; 1H NMR (300 MHz, CDCl3) δ7.23 (s, 2H), 7.15 (s, 1H), 2.98-3.07 (m, 1H), 2.75-2.93 (m, 3H), 2.48-2.67 (m, 2H), 2.36-2.47 (m, 1H), 2.05-2.16 (m, 1H), 1.49 (s,3H); MS (FD)m/z 261 (M+); UV λmaxEtOH (nm) (ε) 203 (20595), 294 (6036).
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]2[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:14]=12)C1C=CC=CC=1.C(N(CC)CC)C.[H][H]>[Pd].CO>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:15]2[C:14]3[C:9](=[O:8])[NH:10][N:11]=[CH:12][C:13]=3[CH:17]=[C:16]2[CH3:18])=[CH:25][CH:24]=1
Reactant: [H][H]
Reactant: COc1ccc(Cn2c(C)cc3c(Cl)nnc(OCc4ccccc4)c32)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(Cn2c(C)cc3cn[nH]c(=O)c32)cc1
Yield: 69 %

Procedure:
38.3 g (97 mmol) of 7-benzyloxy-4-chloro-1-(4-methoxybenzyl)-2-methylpyrrolo[2,3-d]pyridazine (contaminated with about 5% of the isomeric 4-benzyloxy compound), 15 ml of triethylamine and 3.0 g of palladium (5%)/carbon catalyst are hydrogenated with hydrogen for 10 h in 3 1 of methanol. Purification: crystallization from methanol. Yield: 69%, m.p.: 212°-213° C.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:28][O:29]C(OC)(OC)OC>C(O)(=O)C>[CH2:1]([S:5]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:28]([OH:29])[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[C:12]=2[CH:11]=1)=[O:27])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Product: CCCCS(=O)(=O)NC(=O)c1ccc2nc(O)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 0.220 mg of N-1-butanesulfonyl-4-amino-3-(2,4-dichlorobenzylamino)benzamide, 0.3 ml of tetramethoxymethane and 2.0 ml of acetic acid was stirred at 60° C. for 4 hours. Acetic acid was distilled off under reduced pressure, and the residue was extracted with chloroform and with water. The chloroform layer was concentrated, and 4.0 ml of methanol and 36% hydrochloric acid (4 drops). were added to the residue. The mixture was stirred at 60° C. for 2 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The crystals precipitated were washed with water, and were dried to give 0.207 g of 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-hydroxybenzimidazole (379).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C>[Br:1][C:2]1[C:7]([C:8]2[S:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1Br
Reactant: Nc1ccccc1S
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ncccc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.58 g (34.0 mmol) of 2-bromo-3-pyrdinecarboxaldehyde and 5.5 mL (50.9 mmol) of 2-aminothiophenol were dissolved in 150 mL of acetic acid. The solution was agitated at room temperature for 30 minutes. Next, 19.0 g (40.8 mmol) of lead (IV) acetate was added thereto. The resulting product was agitated at 50° C. for 1 hour. Then, water was added to the acquired reactant. The mixture was extracted with ethyl acetate and treated under reduced pressure to remove the solvent, obtaining 5.55 g (Y=55%) of a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[S:42]([N:45]([CH2:49][CH2:50][O:51][CH2:52][C:53](O)=[O:54])[CH:46]1[CH2:48][CH2:47]1)(=[O:44])=[O:43].[F:56][C:57]1[CH:58]=[C:59]([C:63]2([O:69][CH2:70][CH2:71][N:72]3[CH2:76][CH2:75][CH2:74][CH2:73]3)[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)[CH:60]=[CH:61][CH:62]=1>O1CCCC1>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[S:42]([N:45]([CH:46]1[CH2:48][CH2:47]1)[CH2:49][CH2:50][O:51][CH2:52][C:53]([N:66]1[CH2:65][CH2:64][C:63]([C:59]2[CH:60]=[CH:61][CH:62]=[C:57]([F:56])[CH:58]=2)([O:69][CH2:70][CH2:71][N:72]2[CH2:76][CH2:75][CH2:74][CH2:73]2)[CH2:68][CH2:67]1)=[O:54])(=[O:44])=[O:43]
Reactant: Fc1cccc(C2(OCCN3CCCC3)CCNCC2)c1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)N1CCC(OCCN2CCCC2)(c2cccc(F)c2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
DIPEA (2 eq.) and HATU (1.2 eq.) were added to a solution of tetrahydrofuran and 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)acetic acid [acid K] (1 eq.) at 0° C. 4-(3-Fluorophenyl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidine [amine C] (1.2 eq.) was taken up in tetrahydrofuran (2 ml/mmol) and the solution was rendered basic with DIPEA (2 eq.) and added to the reaction mixture at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The mixture was concentrated to dryness on a rotary evaporator, the residue was taken up in methylene chloride and the mixture was washed with water and sat. sodium chloride solution and dried over sodium sulfate. The organic phase was concentrated and the crude product was purified by means of column chromatography (5% methanol in methylene chloride). Yield: 60%. MS, Rt=3.6 min, m/z=622.4 [MH]+
Reaction SMILES: [CH2:1]([NH:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]4[C:23]=3[CH3:24])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2].Cl>[Pd].CO>[CH2:1]([NH:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]4[CH2:22][CH2:21][CH2:20][CH2:19][N:18]4[C:23]=3[CH3:24])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: CCNc1nc2ccc(CCc3nc4ccccn4c3C)cc2o1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCNc1nc2ccc(CCc3nc4n(c3C)CCCC4)cc2o1
Yield: 81 %

Procedure:
10% Palladium on carbon (0.2 g) was added to a mixture of 2-ethylamino-6-[2-(3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.5 g) in methanol (10 ml) and 1N-hydrochloric acid (10 ml) and the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was concentration and the residue was triturated with diethyl ether. The precipitate was collected by filtration and dried to give 2-ethylamino-6-[2-(3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)-ethyl]benzoxazole (0.41 g).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[CH3:31][O:32][C:33]1[C:34]([CH3:43])=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2.C[Si](Cl)(C)C.CCOC(C)=O>CN(C=O)C>[CH3:31][O:32][C:33]1[C:34](/[CH:43]=[CH:1]/[C:3]2[N:4]=[C:5]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[N:7][N:6]3[C:17]=2[C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:20][CH:19]=2)=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2
Reactant: COc1cc2ccccc2nc1C
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2ccccc2nc1/C=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a mixture of compound 5f (100 mg, 0.245 mmol) and 3-methoxy-2-methylquinoline (212 mg, 1.22 mmol) in 4 mL of DMF was added TMSCl (312 μL, 2.45 mmol) dropwise. The resulting mixture was stirred at 90° C. for 24 h. After cooling to rt, the mixture was treated with 60 mL of EtOAc and washed with water (3×20 mL), brine (15 mL) and then dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0:1-1:9 EtOAc/DCM) to afford compound 63a as a yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.10-8.25 (m, 4H), 7.99 (d, J=5.9 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.1 Hz, 1H), 7.49-7.55 (m, 1H), 7.39-7.47 (m, 1H), 7.37 (s, 1H), 6.11 (d, J=5.6 Hz, 1H), 4.04-4.12 (m, 4H), 3.96-4.04 (m, 4H), 4.01 (s, 3H), 1.64 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C33H33N5O4, 564.3 (M+H). found 564.5.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:18][CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](O)=[O:21])=[O:17])=[CH:10]2.CO>C(Cl)(Cl)Cl>[CH2:1]([NH:5][C:20]([CH:19]([NH:18][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)=[O:17])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCCCN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCNC(=O)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 83 %

Procedure:
n-Butyl amine (0.66 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.60 mmol) were coupled according to procedure A (0-25° C. reaction temperature). The crude product was dissolved in chloroform and methanol and the resulting solution stirred 18 hours with 50 mg dimethylaminopyridine-polystyrene resin (Fluka Chemical Co.), the solution filtered, concentrated and the solids triturated with ether: Yield 83%; HPLC (60/40) 8.88 minutes (92%); mp 192-193° C.; TSPMS 398/400 (MH+,100%);
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([CH3:14])[O:11][C@H:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C@H:10]1[O:11][C@H:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@@H](C(F)(F)F)O1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CNC[C@@H](C(F)(F)F)O1
Yield: 67.4 %

Procedure:
N-benzyl-trans-2-trifluoromethyl-6-methylmorpholine [1223452-62-7] (7.5 g, 28.93 mmol) was added to a suspension of Pd/C 10% (1 g) in methanol (150 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere until 1 equivalent of hydrogen was absorbed. The catalyst was removed by filtration over diatomaceous earth. The solvent was evaporated, yielding 3.3 g (67%) of Intermediate 30 as an oil that was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:4][C:5]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1.[H][H]>FC(F)(F)C(O)=O.[Pd]>[F:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:4][C:5]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: CCOC(=O)c1c(=O)c2cc(F)c(N3CCN(C)CC3)cc2n2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c2n(c3cc(N4CCN(C)CC4)c(F)cc3c1=O)CCCC2
Yield: 90.5 %

Procedure:
A mixture of 0.35 g of ethyl 8-fluoro-9-(4-methyl-1-piperazinyl)-6-oxo-6H-benzo[c]quinolizine-5-carboxylate and 0.47 g of 10% palladium-on-carbon in 50 ml of trifluoroacetic acid was shaken under 40 lb. of hydrogen in a Parr apparatus for 18 hours. The mixture was filtered and the solvent evaporated. The concentrate was partitioned between aqueous potassium carbonate and dichloromethane. The organic layer was dried and the solvent removed giving 0.32 g of the desired compound, mp 163°-165° C.
Reaction SMILES: ClC1C=CC(N2CCN(C3N=C(N[C@H](C(C)C)CO)C4[S@](=O)CCC=4N=3)CC2)=CC=1.Cl[C:32]1[C:33]2[S@:53](=[O:54])[CH2:52][CH2:51][C:34]=2[N:35]=[C:36]([N:38]2[CH2:43][CH2:42][N:41]([C:44]3[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=3)[CH2:40][CH2:39]2)[N:37]=1.[CH3:55][O:56][C:57](=[O:63])[C@@H:58]([CH:60]([CH3:62])[CH3:61])[NH2:59]>>[CH3:55][O:56][C:57](=[O:63])[C@H:58]([NH:59][C:32]1[C:33]2[S@:53](=[O:54])[CH2:52][CH2:51][C:34]=2[N:35]=[C:36]([N:38]2[CH2:43][CH2:42][N:41]([C:44]3[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=3)[CH2:40][CH2:39]2)[N:37]=1)[CH:60]([CH3:62])[CH3:61]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: O=[S@@]1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Agent: CC(C)[C@H](CO)Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1[S@](=O)CC2
Product: COC(=O)[C@H](Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1[S@](=O)CC2)C(C)C
Yield: 85 %

Procedure:
The procedure for the formation of (R)-2-{(R)-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino}-3-methyl-butan-1-ol (with the exception of omitting the IPA recrystallization) was followed, starting with (R)-4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine-5-oxide and D-valine methyl ester (1.3 equiv). This resulted in the crude product being obtained in 85% yield. 1H NMR (500 MHz, CDCl3) δ 7.18-7.26 (m, 2H), 6.82-6.90 (m, 2H), 5.78 (d, J=6.5 Hz, 1H), 4.59 (dd, J=7.0, 7.0 Hz, 1H), 3.98 (bs, 4H), 3.72 (s, 3H), 3.62 (ddd, J=7.5, 7.5, 15.0 Hz, 1H), 3.36 (ddd, J=8.0, 8.0, 15.0 Hz, 1H), 3.10-3.20 (m, 4H), 2.95-3.10 (m 2H), 2.23 (m, 1H), 1.00-1.07 (m, 6H); 13C NMR (500 MHz, CDCl3) δ 174.8, 172.8, 163.1, 159.8, 150.2, 129.4, 125.4, 118.0, 109.0, 59.6, 59.5, 52.3, 50.4, 49.7, 44.1, 33.0, 31.3, 19.4, 19.1 (3 signals missing due to overlap). LCMS (ESI) for C22H29ClN5O3S (M+H)+: calcd. 478.2, obsvd. 478.1.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:7]1)[CH3:2].[CH2:21]([O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([CH2:31]Br)[CH:28]=[CH:27][C:26]=1[O:33][CH3:34])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([CH2:31][N:18]2[CH2:17][CH2:16][CH:15]([C:8]3[C:9]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:7]=3)[CH2:20][CH2:19]2)[CH:28]=[CH:27][C:26]=1[O:33][CH3:34])[CH3:22]
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: CCOCCn1cc(C2CCNCC2)c2cccnc21
Product: CCOCCn1cc(C2CCN(Cc3ccc(OC)c(C(=O)OCC)c3)CC2)c2cccnc21

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 0.73 g (2.67 mmol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 0.88 g (3.20 mmol) of 5-bromomethyl-2-methoxybenzoic acid ethyl ester. After standard work-up and purification, 0.38 g (31% of yield) of the expected product were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[N:19]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][N:20]=1>>[N:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:10][CH:11]=2)=[O:26])=[CH:21][N:20]=1
Reactant: NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: O=C(O)c1ccnnc1
Product: O=C(NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1)c1ccnnc1

Procedure:
By treating 6-[4-(4-aminobutyl)phenyl]pyridazin-3(2H)-one and pyridazin-4-carboxylic acid in the same manner as in Example 87, 6-[4-[4-(pyridazin-4-ylcarbonylamino)butyl]-phenyl]pyridazin-3(2H)-one was obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([OH:13])=[C:5]2[C:4]1=[O:19])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([O:13][CH3:20])=[C:5]2[C:4]1=[O:19])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(CC)C[C@@H]2C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(c1OC)C(=O)N(CC)C[C@@H]2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (4S)-2-ethyl-8-hydroxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-carboxylate (6.6 g, 24.8 mmol), anhydrous potassium carbonate (13.7 g, 99.1 mmol, 325 mesh), and iodomethane (4.2 g, 29.7 mmol) in anhydrous DMF (123 mL) was stirred at room temperature overnight. The mixture was filtered and concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a gradient of 0-3% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound. Residual methanol was removed by concentrating from its solution in toluene under vacuum.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=1>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:64]=1
Reactant: COc1ccc(OC)c(-c2cccc(N)c2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC)c(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.4 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,5′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.02 g of product in 64% yield: LCMS (ESI) m/z 486 (MH+).