Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.F[C:20](F)(F)[C:21](O)=O>ClCCl>[O:1]=[C:2]1[N:6]([CH:7]([C:21]2[CH:20]=[CH:15][CH:5]=[CH:4][CH:18]=2)[C:8]([OH:10])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccccc1)n1c(=O)[nH]c2ccccc21
Temperature: 25 °C

Procedure:
1.00 g (3.08 mmol) of tert-butyl (2-oxo-2,3-dihydrobenzimidazol-1-yl)acetate (XId) was dissolved in dichloromethane (10 ml) and, while stirring at room temperature, trifluoroacetic acid (6 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 827 mg (100%) of white solid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=2)[N:10]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:21][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: NC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 10.5 %

Procedure:
To a solution of 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzamide (Intermediate-17, 0.100 g, 0.301 mmol) in dry toluene (5 mL) was added 1-bromo-4-(trifluoromethyl)benzene (0.101 g, 0.451 mmol), sodium tert-butoxide (0.058 g, 0.602 mmol), tris(diphynylideneacetone)dipalladium(0) (0.005 g, 0.0006 mmol), 4,5 bis(diphenylphosphino) and 9,9-dimethylxanthene (0.005 g, 0.0009 mmol) under nitrogen atmosphere. The reaction mass was refluxed for 3-4 h. The reaction mass was quenched in water and extracted in ethyl acetate. The organic layer was concentrated to afford crude product which was purified by column chromatography to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.40 (br s, 1H), 7.84 (t, J=9 Hz, 1H), 7.55 (d, 1H), 7.72-7.75 (m, 3H), 8.02 (d, J=8.1 Hz, 2H), 8.11 (br s, 3H) 10.61 (br s, 1H), 12.70 (br s, 1H). MS (m/z): 475.18 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:26][CH2:27][CH:28](O)[CH2:29][F:30]>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:28]([CH2:29][F:30])[CH2:27][F:26])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC(CF)CF
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC(CF)CF)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 1,3-difluoro-2-propanol in analogy to Example 9c): MS (ISN): 438.1 (M−H)−.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:35])C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1>>[CH3:35][NH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cccnc1
Product: CN[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 99.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6) tR=0.8 min, m/z=458.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=1
Reactant: O=Cc1ccccn1
Reactant: NCCCc1ccc2ccccc2c1Cl
Product: Clc1c(CCCNCc2ccccn2)ccc2ccccc12
Yield: 67 %

Procedure:
Prepared from 3-(1-chloronaphthalen-2-yl)propan-1-amine and pyridine-2-carbaldehyde in 67% yield as a yellow oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:29][C:30]1[CH:31]=[C:32]([NH:36][C:37](=[O:62])[CH2:38][N:39]2[CH:43]=[C:42]([NH:44][C:45]3[C:54]4[C:49](=[CH:50][C:51]([O:55][CH2:56][CH:57]5[CH2:61][CH2:60][NH:59][CH2:58]5)=[CH:52][CH:53]=4)[N:48]=[CH:47][N:46]=3)[CH:41]=[N:40]2)[CH:33]=[CH:34][CH:35]=1.[Si:63]([O:70][CH2:71][CH:72]=O)([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64].[OH-].[Na+]>O1CCCC1.CO.C(O)(=O)C>[Si:63]([O:70][CH2:71][CH2:72][N:59]1[CH2:60][CH2:61][CH:57]([CH2:56][O:55][C:51]2[CH:50]=[C:49]3[C:54]([C:45]([NH:44][C:42]4[CH:41]=[N:40][N:39]([CH2:38][C:37]([NH:36][C:32]5[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=5)=[O:62])[CH:43]=4)=[N:46][CH:47]=[N:48]3)=[CH:53][CH:52]=2)[CH2:58]1)([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64]
Reactant: O=C(Cn1cc(Nc2ncnc3cc(OCC4CCNC4)ccc23)cn1)Nc1cccc(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCN1CCC(COc2ccc3c(Nc4cnn(CC(=O)Nc5cccc(F)c5)c4)ncnc3c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium triacetoxyborohydride (0.23 g, 1.1 mmol) was added to a mixture of N-(3-fluorophenyl)-2-(4-{[7-(pyrrolidin-3-ylmethoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetamide bis(trifluoroacetate) (0.30 g, 0.44 mmol) and (tert-butyldimethylsilyloxy)acetaldehyde (0.20 ml, 1.0 mmol) in tetrahydrofuran (9 ml) and methanol (3 ml) containing a catalytic amount of acetic acid. The mixture was stirred at room temperature for 1 hour. The mixture was poured into sodium hydroxide solution (1M) and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulphate and then evaporated to leave a brown oil which was purified by silica gel chromatography. Elution with 3 to 6% methanol in dichloromethane gave 2-{4-[(7-{[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyrrolidin-3-yl]methoxy}quinazolin-4-yl)amino]-1H-pyrazol-1-yl}-N-(3-fluorophenyl)acetamide. MS (+ve ESI): 620 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1>>[OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([N:11]([CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=3)=[O:21])[CH2:18][CH2:19]2)[CH3:10])=[O:9])[CH:3]=1
Reactant: O=C(O)c1cc(O)[nH]n1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1cc(O)[nH]n1

Procedure:
The title compound was prepared from commercially available 5-hydroxy-1H-pyrazole-3-carboxylic acid and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) analogously to Example 15 step 3;
Reaction SMILES: CC(C)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][S:16][CH2:17][CH:18]=2)=[C:9]([F:19])[CH:8]=1.[C:22]([O:25][C@H:26]([CH2:32]Cl)[CH2:27][NH:28][C:29](=[O:31])[CH3:30])(=[O:24])C.CC(C)([O-])C.[Li+].C(O)(=O)C>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CO.C1(C)C=CC=CC=1>[S:16]1[CH2:15][CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:32][C@H:26]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:25][C:22]3=[O:24])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1
Reactant: CC(C)COC(=O)Nc1ccc(C2=CCSCC2)c(F)c1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Temperature: 15 °C
Reaction time: 17 h
Yield: 78.5 %

Procedure:
To a mixture of [4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamic acid 2-methylpropyl ester (17.89 g, 57.83 mmol), (S)-N-[2-(acetyloxy)-3-chloropropyl]acetamide (22.35 g, 115.42 mmol, 2.00 eq), methanol (3.66 g, 114 mmol, 1.97 eq), 2,6-di-tert-butyl-4-methylphenol (0.1365 g, 0.6194 mmol, 0.0107 eq), toluene (52 ml), isooctanes (49 ml), and N,N-dimetlhylformamide (34.3 ml) is added a solution of lithium t-butoxide (I 3.94 g, 174.1 mmol, 3.01 eq) in isooctanes (130 ml) over 1.6 h while maintaining 15° C. Isooctanes (20 ml) is added and the mixture stirred at 15 to 19° C. for 17 h. The mixture is cooled to 0° C. and acetic acid (6.7 ml, 117 mmol, 2.02 eq) added. The mixture is warmed to 21° C. and methanol (29 ml) added. The phases are separated and the upper washed twice with a mixture of methanol (29 ml) and water (9 ml). To the combined lower phases is added water (69 ml) and methylene chloride (69 ml). The phases are separated and the upper phase washed twice with methylene chloride (29 ml). The combined lower phases are concentrated under reduced pressure to 112 ml total volume. Methanol (69 ml) is added and the mixture concentrated to 112 ml. Methanol (69 ml) is added and the mixture concentrated to 75 ml then toluene (65 ml) is added. Water (65 ml) is added over ½ h while maintaining 19 to 30° C. The mixture is cooled to 9° C. and isooctanes (56 ml) added. The slurry is cooled to 0° C. and the precipitate collected by vacuum filtration, washed with water (22 ml) and isooctanes (22 ml) and dried in a nitrogen stream to give the title compound (15.909 g, 78.5%): HPLC retention time=2.77 min (column=Phenomenex Luna 5.0 micron C-8(12) 150×4.6 mm, flow rate=2.0 min/min, gradient elution from 40:60 A:B to 73.3:26.7 A:B over 15 minutes; A=acetonitrile; B=water).
Reaction SMILES: [CH:1]1([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[CH:1]1([C:6]2[N:7]([CH2:16][C:17]3[CH:36]=[CH:35][C:20]4/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=5[O:24][CH2:25][C:19]=4[CH:18]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: c1ccc2[nH]c(C3CCCC3)nc2c1
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CCCC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 95.3 %

Procedure:
Using 2-cyclopentyl-1H-benzo[d]imidazole (62 mg, 0.335 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (148 mg, 95%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[C:8](SCC)=[N:7][C:6]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH3:2]>[Ni].C(O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(SCC)nc1NCc1ccc(OC)cc1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cc(F)cnc1NCc1ccc(OC)cc1
Yield: 92.8 %

Procedure:
Freshly activated raney nickel (50 g) was added to a solution of 6-ethylsulfanyl-5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester (67) (31 g, 85 mmol) in anhydrous ethanol and refluxed for 48 h. The solution was cooled and filtered through celite. The filtrate was evaporated under reduced pressure to yield 24 g (93%) of 5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester (68) as a viscous oil which solidified to a white solids after keeping several days under vacuum at room temperature. Mp 90° C. 1H-NMR (DMSO-d6): δ 1.30 (t, J=7.2 Hz, 3H), 3.71 (s, 3H), 4.29 q, J=7.2 Hz, 2H), 4.55 (d, J=5.6 Hz, 2H), 6.87 (m, 2H), 7.26 (m, 2H), 7.96 (dd, J=3.2, 8.8 Hz, 1H), 8.12 (m, 1H), 8.35 (d, J=3.2 Hz, 1H); EIMS m/z 305 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:13]([O:21][CH3:22])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].CN([CH:26]=[O:27])C>>[CH:16]1([O:15][C:14]2[C:5]([N:4]([CH2:17][CH2:16][O:15][CH:14]3[CH2:13][CH2:12][CH2:11][CH2:26][O:27]3)[C:1](=[O:3])[CH3:2])=[C:6]([CH:11]=[CH:12][C:13]=2[O:21][CH3:22])[C:7]([O:9][CH3:10])=[O:8])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N(CCOC1CCCCO1)C(C)=O

Procedure:
Methyl 3-(cyclopentyloxy)-4-methoxy-2-(N-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido)benzoate was prepared from methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate (Example 1, Step 4) following the procedure outlined in Example 4 (except: solvent was DMF; temp was 33° C.; time was overnight). MS (ESI): 458.2 (M+Na).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOCC.O>[CH2:18]([O:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(OCc1ccccc1)c1ccc(Cl)cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 7.0 g (40.6 mmol) 2-hydroxy-4-chlorobenzoic acid in 150 ml of dry DMF was added 16.8 g (122 mmol) of K2CO3 followed by the dropwise addition of 15.2 g (89.2 mmol) of benzyl bromide. The reaction mixture was warmed to 50° C. and stirred overnight. After 16h, the reaction mixture was diluted with Et2O and H2O and the layers were separated. The aqueous layer was extracted with Et2O (2×) and the combined organic layers were successively washed with 1N HCl (3×100 ml), saturated NaHCO3 solution (2×50 ml) and brine (1×50 ml). The solution was dried over anhydrous MgSO4 and concentrated to give 2-benzyloxy-4-chlorobenzoic acid, benzyl ester as a pale yellow solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][C:14](=O)[C:13]3(C)[CH3:19])=[CH:8][C:6]=2[N:7]=1.[N:27]1C=CN2CCNC[C:31]=12>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[CH:14]=[CH:31][N:27]=[C:19]4[CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: c1cn2c(n1)CNCC2
Reactant: CC1(C)C(=O)NCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCn4ccnc4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3,3-dimethyl-piperazin-2-one using 5,6,7,8tetrahydro-imidazo[1,2-a]pyrazine in place of 3,3-dimethyl-piperazin-2-one. The title compound was obtained as a pale brown solid (50 mg, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:5]([CH:19]=[N:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:4]=1.CO.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:5]([CH2:19][NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:4]=1
Reactant: COc1ccc(OCCCN2CCOCC2)c(C=NCCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(OCCCN2CCOCC2)c(CNCCc2ccccc2)c1
Temperature: 35 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
A stirred solution of 4-[3-[4-methoxy-2-[[(2-phenylethyl)imino]methyl]phenoxy]propyl]-morpholine (41.7 g) in 190 ml. of methanol is reduced with 12.4 g of sodium borohydride (added portionwise). A cold water bath is used to maintain the temperature of the reaction mixture at 35° C. After 3 hours, the solvent is treated with water and the product is extracted two times with ether. The ether fractions are combined, treated with water, dried and concentrated to give 33.3 g of the title compound, boiling point 249°-254° C. at 0.3-0.4 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:4]=2)=[O:10])=[CH:12][CH:13]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to tert-butylamine via Procedure G. The product was purified on reverse phase HPLC to yield N1-tert-butyl-N4-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 408 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][N:19]=3)[C:16](=O)[C:15]3[C:14]([C:25]([O:27]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:31][NH:32][C:25](=[O:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:22]([CH3:23])[CH:21]=[N:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nncn1C)C(c1ccc(F)cc1)N2
Solvent: O
Solvent: CO
Product: Cn1cnnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg) in 85% hydrazine monohydrate (2 mL) and methanol (5 mL) was stirred at room temperature for 4 h. Then the solution was evaporated, the crude product was purified by prep-HPLC to obtain the title compound as a white solid (20 mg, yield 18%). LC-MS (ESI) m/z: 363 (M+1)+. 1H-NMR (400 MHz, DMSO-d) δ (ppm): 3.50 (s, 3H), 4.83-4.86 (d, J=11.6 Hz, 1H), 5.00-5.03 (d, J=11.6 Hz, 1H), 7.12-7.19 (m, 3H), 7.39-7.42 (m, 2H), 7.47-7.51 (m, 2H), 7.60-7.64 (t, J=8 Hz, 1H), 8.31 (s, 1H), 12.24 (s, 1H).
Reaction SMILES: [C:1]1([PH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[P:16]([CH2:29][CH2:30][CH2:31]Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Li]>C1COCC1.O>[P:16]([CH2:29][CH2:30][CH2:31][PH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCCP(c1ccccc1)c1ccccc1
Reactant: Pc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(PCCCP(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
In a Schlenk flask were placed phenylphosphine (3.3806 g, 30.71 mmol) with THF (60 ml) and chilled to −30° C. in a freezer over 30 minutes. To this solution was added lithium diisopropylamide (16 ml, 32.16 mmol) and the resulting solution was allowed to warm to room temperature while stirring. In a 250 ml Schlenk flask was placed (C6H5)2P(CH2)3Cl (7.9089 g, 30.1 mmol) in 100 ml THF and the solution was cooled to −78° C. The lithium phenylphosphide solution was added to the (C6H5)2P(CH2)3Cl solution at such a rate that the temperature of the solution remained constant at −78° C. After addition, the solution was slowly warmed to room temperature. Degassed DI water (0.2 ml) was added to the dark orange solution. The color changed to yellow-orange. The solvents were removed in vacuo. The resulting gel was dissolved in toluene and filtered through Celite. Toluene was then removed in vacuo, leaving an orange-yellow oil. Yield: 10.0 g (99.1%). 31P{1H} NMR (CDCl3, 122 MHz, δppm: −16.30 and −52.86 (>99% pure). 1H NMR (CDCl3, 400 MHz, δ: 1.58–2.15 (3 complex peaks integrated to ˜7Hs), 4.12 (d of t, H—P) and 7.26–7.43 (complex pattern).
Reaction SMILES: COC([C@@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=S)CC(=O)C)=O.COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=S)CC(=O)C)=O.Cl.N(C1C=C(NC(=O)C)C=CC=1)N.[CH3:70][O:71][C:72]([C@H:74]1[CH2:78][C@@H:77]([S:79]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][C:83]=2[C:88]([F:91])([F:90])[F:89])(=[O:81])=[O:80])[CH2:76][N:75]1[C:92]1[N:93]([C:98]2[CH:103]=[CH:102][CH:101]=[C:100]([NH:104][C:105](=[O:107])[CH3:106])[CH:99]=2)[N:94]=[C:95]([CH3:97])[CH:96]=1)=[O:73]>>[CH3:70][O:71][C:72]([C@@H:74]1[CH2:78][C@@H:77]([S:79]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][C:83]=2[C:88]([F:89])([F:91])[F:90])(=[O:81])=[O:80])[CH2:76][N:75]1[C:92]1[N:93]([C:98]2[CH:103]=[CH:102][CH:101]=[C:100]([NH:104][C:105](=[O:107])[CH3:106])[CH:99]=2)[N:94]=[C:95]([CH3:97])[CH:96]=1)=[O:73]
Reactant: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(NC(C)=O)c1
Agent: CC(=O)Nc1cccc(NN)c1
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(NC(C)=O)c1

Procedure:
In analogy to the procedure described in example 308d, a mixture of (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) and of (2R,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with N-(3-hydrazino-phenyl)-acetamide hydrochloride (CAS Reg. No. 1187369-44-3) to give a mixture of the title compound and (2R,4R)-1-[2-(3-acetylamino-phenyl)-5-methyl-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as yellow solid. MS (ESI): m/z=551.2 [M+H]+.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[CH:3][CH:2]=1.B(Br)(Br)Br.ClCl>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[CH:3][CH:2]=1
Reactant: COc1cccc2c1cc(C)n2Cc1ccc(-c2ccccc2)cc1
Agent: BrB(Br)Br
Agent: ClCl
Product: Cc1cc2c(O)cccc2n1Cc1ccc(-c2ccccc2)cc1
Yield: 77.4 %

Procedure:
By the method used in Example 1, Part D, 1.3 g (4.0 mmol) of 1-([1,1'-biphenyl]-4-ylmethyl)-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 16 mL of 1M BBr3 /CH2 Cl2 to give 970 mg (77% yield) of crude 1-([1,1'-biphenyl]-4-ylmethyl)-4-hydroxy-2-methyl-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1.[CH:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH2:25])[CH:17]=1.Cl>>[ClH:1].[CH2:12]([C:4]1[CH:3]=[C:2]([NH:25][C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:16][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCCCc1cc(Cl)c2ccccc2n1
Agent: Cl
Product: CCCCc1cc(Nc2ccc(C(=O)O)cc2)c2ccccc2n1
Yield: 60.8 %

Procedure:
0.840 g of the product of Step D of Example 3 and 0.640 g of amino benzoic acid were introduced into 15 ml of 1N hydrochloric acid and the solution was refluxed for 3 hours. The precipitate was filtered, washed with water and dried at 60° C. under reduced pressure to obtain 0.830 g of the expected product.