Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31]([OH:33])=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:67])[C:58]2[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:59]=2[Br:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[Br:66][C:59]1[CH:60]=[CH:61][C:62]([O:64][CH3:65])=[CH:63][C:58]=1[C:57]([N:54]1[CH2:53][CH2:52][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:31]([C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:30][N:29]=2)=[O:33])[CH2:56][CH2:55]1)=[O:67]
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Reactant: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CN)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)on3)CC2)c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
HOBt (21.5 mg, 0.16 mmol) and DIPEA (66 mg, 0.51 mmol) were added to a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid (24 mg, 0.13 mmol) in DMF (1.0 mL). The mixture was then cooled to 10° C. and EDCI.HCl (30.5 mg, 0.16 mmol) followed by 2-amino-1-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-ethanone hydrochloride (50 mg, 0.13 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the resulting precipitate was isolated by filtration under reduced pressure and dried to afford 5-phenyl-isoxazole-3-carboxylic acid {2-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid in 53.8% yield. LC-MS purity: 92.97%, 1H-NMR (DMSO): δ 8.7 (t, 1H), 8.0 (m, 2H), 7.58 (m, 4H), 7.41 (s, 1H), 7.0 (m, 2H), 4.2 (m, 2H), 3.78 (s, 3H), 3.5 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].CN1CCNCC1[Al+]C1CNCCN1C.CCOCC>O1CCCC1>[C:1]([NH:8][C:9]([CH3:14])([CH3:13])[CH2:10][OH:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN1CCNCC1[Al+]C1CNCCN1C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CO)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
N-Boc-aminoisobutyric acid is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over NaSO4 and evaporated to yield N-Boc-2-amino-2-methylpropanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]#[C:15][CH2:16][OH:17])=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[C].[Pd].C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH:10]([C:18]([O:20][CH3:21])=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C#CCO)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1CN(Cc2ccccc2)CCC1CCCO
Reaction time: 2 h

Procedure:
To 40 mL of an ethanol solution containing 2.6 g of methyl 1-benzyl-4-(3-hydroxy-1-propin-1-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate, 1.0 g of palladium carbon was added, and the mixture was stirred for 2 hours under a hydrogen atmosphere. Thereto was added 0.7 g of palladium carbon, and the mixture was stirred for 2 hours under a hydrogen atmosphere. The insoluble material filtered off, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate 1:2] to obtain 0.50 g of a brown oily substance, methyl 1-benzyl-4-(3-hydroxypropyl)piperidine-3-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([OH:3])=[O:2].[C:13]([O-])(O)=O.[Na+].CI.O>CN(C=O)C.CCOC(C)=O>[CH3:13][O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)=[O:3]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-carboxyindole (32.2 g, 0.2 mol), NaHCO3 (53.36 g, 0.64 mol), methyl iodide (122.22 g, 0.86 mol) in 60 mL of DMF were stirred at RT for 2 days. Water and EtOAc are added, and the organic layer was washed with bicarbonate solution, dried and concentrated to obtain 5-(methoxycarbonyl)indole. 1H NMR (DMSO) δ: 11.44 (s, 1H), 8.22 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.37˜7.47 (m, 2 H), 6.56 (d, J=2.0 Hz, 1H), 3.80 (s, 3H). MS (ESI) m/e (M+H+): 176.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:35][NH:34][CH2:33]2)=[N:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH2:37]([O:39][C:40]1[N:45]=[CH:44][C:43]([C:46]2([OH:53])[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH3:38]>>[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:33][N:34]([CH:49]3[CH2:50][CH2:51][C:46]([C:43]4[CH:44]=[N:45][C:40]([O:39][CH2:37][CH3:38])=[CH:41][CH:42]=4)([OH:53])[CH2:47][CH2:48]3)[CH2:35]2)=[N:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCOc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C(=O)NC(C)(C)C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide TFA salt (as prepared in Example 81, Step D) and 4-(6-ethoxy-pyridin-3-yl)-4-hydroxy-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C=CC2N(O)N=NC=2C=1.[C:54]([C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][C:66]([C:69](O)=[O:70])=[CH:65][CH:64]=2)=[CH:59][CH:58]=1)(=[O:56])[CH3:55]>C(Cl)Cl.C(Cl)CCl>[ClH:1].[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:69]([C:66]3[CH:65]=[CH:64][C:63]([C:60]4[CH:61]=[CH:62][C:57]([C:54](=[O:56])[CH3:55])=[CH:58][CH:59]=4)=[CH:68][CH:67]=3)=[O:70])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: C=Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc(C(=O)N3CCCN(C4CCC4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.6 %

Procedure:
1-(Cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) (0.15 g) was stirred with diethylaminomethyl polystyrene (1.0 g), HOBT (0.045 g) and 4′-acetyl-4-biphenylcarboxylic acid (0.13 g) in DCM (5 ml). EDC (0.16 g) was then added and the reaction stirred at rt for 16 h. The polymer supported base was filtered off and the filtrate was diluted with DCM (10 ml) and washed with saturated sodium hydrogen carbonate (2×15 ml). The organic layer was loaded directly onto a silica column eluting with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM. The isolated free base product was dissolved in DCM (5 ml) and treated with excess 1N HCl/diethyl ether solution (1 ml) and stirred for 10 min. The mixture was evaporated (co-evaporated with acetone 2×10 ml), triturated with acetone, then dried at 50° C. under high vacuum for 16 h to yield the title compound (E2) as a pale solid (0.055 g). MS electrospray (+ion) 377 (MH+). 1H NMR δ (DMSO-d6): 10.57 (1H, s), 9.07 (2H, d, J=6.4 Hz), 7.88 (4H, m), 7.60 (2H, d, J=7.6 Hz), 4.15 (1H, m), 3.82-3.33 (6H, m), 3.02 (2H, m), 2.62 (3H, s), 2.41-1.62 (8H, m).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([CH2:8][OH:9])[CH2:6][CH:5]([OH:10])[CH2:4]1)[CH3:2].Br([O-])(=O)=O.[K+].CCOCC>CC#N.O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>[CH2:1]([C@H:3]1[C@@H:7]([CH2:8][OH:9])[CH2:6][C:5](=[O:10])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1CC(O)C[C@@H]1CO
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CC[C@@H]1CC(=O)C[C@@H]1CO
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a solution of (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanol (4.00 g, 27.7 mmol) in MeCN (70 mL) and water (30.0 mL) was added potassium bromate (1.487 mL, 29.1 mmol) and CAN (0.760 g, 1.387 mmol). The reaction mixture was heated to about 80° C. After about 2 h, the reaction mixture was cooled to rt and Et2O (100 mL) was added. The organic layer was separated, washed with brine (30 mL), concd in vacuo and purified by chromatography on silica gel eluting with EtOAc/heptane (20-60%) to provide (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanone (2.4 g, 61%) as an oil. 1H NMR (400 MHz, CDCl3) δ 3.79 (dd, J=10.5, 5.3 Hz, 1H), 3.70 (dd, J=10.5, 6.5 Hz, 1H), 2.55-2.44 (m, 1H), 2.41-2.25 (m, 4H), 2.15-2.05 (m, 1H), 1.55-1.65 (m, 2H), 1.43-1.30 (m, 1H), 0.97 (t, J=7.3 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:15]([CH:16]2C[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH2:14][C:6]2[C:7]3[CH:8]=[N:9][NH:10][C:11]=3[CH:12]=[CH:13][C:5]=2[CH2:4][C@H:3]1[NH:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:48])[CH2:34][CH2:33]1)=[O:31].FC(F)(F)C(O)=O>ClCCl>[O:48]=[C:39]1[N:38]([CH:35]2[CH2:36][CH2:37][N:32]([C:30]([NH:29][C@H:3]3[C:2](=[O:1])[N:15]([CH:16]4[CH2:17][CH2:18][NH:19][CH2:20]4)[CH2:14][C:6]4[C:7]5[CH:8]=[N:9][NH:10][C:11]=5[CH:12]=[CH:13][C:5]=4[CH2:4]3)=[O:31])[CH2:33][CH2:34]2)[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(C2CCNC2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
(R)-tert-butyl 4-(8-oxo-7-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-7,8-dihydroazepino[3,4-e]indazol-9(3H,6H,10H)-yl)piperidine-1-carboxylate (45 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (0.25 mL)was added to the mixture. Reaction stirred at room temperature for 1.5 hour. Reaction mixture was concentrated in vacuo. C18 preparatory HPLC purification afforded the title compound as yellow solid in 52% yield. High resolution MS m/e (M+H)+=543.2830.
Reaction SMILES: FC(F)(F)C(O)=O.C[N:9]([CH:11]=[C:12]([N:18]1[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]1)[C:13]([O:15]CC)=O)C.[CH:25]1([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[C:39]([NH:41]N)[N:38]=[CH:37][N:36]=3)[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1>C(OCC)(=O)C>[CH:25]1([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[N:36]=[CH:37][N:38]=[C:39]([N:41]4[C:13](=[O:15])[C:12]([N:18]5[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]5)=[CH:11][NH:9]4)[CH:40]=3)[CH2:31][CH2:30]2)[CH2:26][CH2:27][CH2:28]1
Reactant: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCN(C5CCC5)CC4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid are added to a mixture of 236 mg (1.0 mmol) of the compound from Example 6A and 250 mg (1.0 mmol) of the compound from Example 9A in 4 ml of ethyl acetate, and the mixture is stirred at 100° C. for 20 h. The reaction mixture is concentrated under reduced pressure, more ethyl acetate and trifluoroacetic acid (the same amounts as above) are added and the mixture is stirred at 100° C. for 3 d. The reaction mixture is cooled to RT, and the precipitated solid is filtered off and washed with diethyl ether. The residue is suspended in 2 ml of water, dissolved by adding aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 219 mg (56% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH2:17][CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:11][O:10]C1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:5][C:6]([NH:8][C@@H:12]([CH2:13][C:14]1([CH2:17][CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:16]1)[CH2:11][OH:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(CCOCc3ccccc3)CC2)COC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1(CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 23.9 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-[1-(2-benzyloxyethyl)cyclopropylmethyl]1,3-oxazolidine, 0.67 g of p-toluenesulfonic acid hydrate and 100 ml of methanol is stirred at room temperature for 5 h. After the reaction mixture has been concentrated, diethyl ether is added. The organic phase is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and added over sodium sulfate. The crude product is purified by means of FC over 900 g of silica gel (mobile phase gradient from E to A): Rf (C)=0.26; anal. calc. for C20H31NO4 : C68.74%, H8.94%, N4.01%; found C68.44%, H8.93%, N4.09%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C.[NH2:47][CH2:48][C:49]1[C:58](=[O:59])[C:57]2[C:52](=[CH:53][C:54]([Cl:60])=[CH:55][CH:56]=2)[N:51]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:50]=1[C:67]([N:69]([CH3:71])[CH3:70])=[O:68]>CN(C=O)C>[CH3:70][N:69]([CH3:71])[C:67]([C:50]1[N:51]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:52]2[C:57]([C:58](=[O:59])[C:49]=1[CH2:48][NH:47][C:11]([C:10]1[CH:9]=[N:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:15][CH:14]=1)=[O:13])=[CH:56][CH:55]=[C:54]([Cl:60])[CH:53]=2)=[O:68]
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(N3CCOCC3)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Morpholinonicotinic acid (32.6 mg, 0.142 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (120 mg, 0.374 mmol) and triethylamine (100 mg, 0.137 mL, 0.988 mmol) were combined with DMF (4 mL). The reaction mixture was stirred at room temperature for 10 min. After this time, 3-(aminomethyl)-7-chloro-N,N-dimethyl-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxamide (intermediate C) (0.052 g, 0.156 mmol) was added. The reaction mixture was stirred at room temperature for 15 hr. The crude material was purified by flash chromatography (10% ethyl acetate-hexanes ramped to 100% ethyl acetate). MS calcd. for C29H28ClN5O4 [(M+H)+] 546.2, obsd. 546.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:24]([OH:26])=O)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][NH2:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][NH:36][C:24]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[C:11]=1[CH:21]([CH3:23])[CH3:22])=[O:26]
Reactant: NCc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ncco3)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ncco3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 42, 244 mg, 0.685 mmol) in CH2Cl2 (12 ml) was added EDC (262 mg, 1.37 mmol) and DMAP (125 mg, 1.03 mmol), followed by 3,4-difluorobenzyl amine (197 mg, 1.03 mmol). The crude material was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH:30]([CH3:32])[CH3:31])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH:30]([CH3:31])[CH3:32])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)O)c(C(C)C)o3)C[C@H]2OC)nc1Cl
Yield: 90.9 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-isopropyl-1,3-oxazole-4-carboxylate obtained in Example (111d) (0.15 g, 0.30 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and THF (5 mL), to obtain 0.12 g of the title compound as a colorless solid (90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:19])(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:12]1[CH:13]=[C:8]([CH:5]2[CH2:6][CH2:7][C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4]2)[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1(C)CCC(c2ccc(O)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(c2ccc(O)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of 4-(4,4-dimethylcyclohexyl)phenol (2.16 g, 10.6 mmol), disiobutylamine (0.14 mL) and sulfuryl chloride (0.59 mL, 7.4 mmol) in toluene was stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature, treated with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vaclio. The resulting oil was subjected to chromatography on silica gel, using hexane/ethyl acetate (20:1), to afford the title compound (1.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[O:17]=[C:18]1[C:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:22]([CH2:39][CH2:40][CH3:41])[N:21]2[N:42]=[CH:43][N:44]=[C:20]2[N:19]1[CH:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1>O1CCCC1>[C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C:23]2[C:18](=[O:17])[N:19]([CH:45]3[CH2:50][CH2:49][C:48](=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:47][CH2:46]3)[C:20]3[N:21]([N:42]=[CH:43][N:44]=3)[C:22]=2[CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=1)#[N:38]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=CC(=O)OCC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution (10 mL) of ethyl(diethoxyphosphoryl)acetate (1.2 g) in tetrahydrofuran was added sodium hydride (0.21 g), and the mixture was stirred at room temperature for 1 hr. A solution (10 mL) of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2 g) in tetrahydrofuran was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with 1 N hydrochloric acid and ethyl acetate, and the obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.9 g, 86%).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[BH4-].[Na+].CCCCCC>C(O)C>[CH2:1]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: CCCCCCCCCOc1ccccc1CO
Temperature: 25 °C
Reaction time: 0.29 h

Procedure:
2-Hydroxybenzaldehyde (110 g), was alkylated by mixing this compound with 1-bromononane (180 g), anhydrous potassium carbonate and dimethylformamide (800 mL). This mixture was heated at 80° C. for 14 hours. Hexane and water were then added and the hexane extract was concentrated and the residue was distilled to yield the 2-nonyloxybenzaldehyde (210 g), bp 121° C. (0.3 mm Hg). A solution of 2-nonyloxybenzaldehyde prepared above (100 g) in ethanol (1000 mL) at 10° C. was reduced by treating with an excess of sodium borohydride (6 g) and after stirring the mixture for a further 15-20 min. at room temperature, the compound 2-nonyloxybenzylalcohol was isolated by extraction into hexane. Removal of the hexane in vacuo yielded the crude 2-nonyloxybenzylalcohol (98 g). The resulting 2-nonyloxybenzylalcohol was added to a mixture of triphenylphosphine hydrobromide (144 g) in acetonitrile (500 mL) and the resultant solution was heated at reflux for 14 hours. Removal of the solvents in vacuo and crystallization of the residue from a tetrahydrofuran/ethyl ether mixture gave the pure [[2-(nonyloxy)phenyl]methyl]triphenylphosphonium bromide (208 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[C:12]([CH3:18])[C:11]=1[CH3:19])=[O:8].[CH2:20](Cl)[C:21](=[CH2:23])[CH3:22]>CN(C)C=O>[CH:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:22][C:21]([CH3:23])=[CH2:20])=[C:12]([CH3:18])[C:11]=1[CH3:19])=[O:8]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(C)c(NC=O)c(C)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
Potassium carbonate (74.0 g, 0.54 mol) was added to a solution of 4-formylamino-2,3,5-trimethylphenol (85.5 g, 0.48 mol) and methallyl chloride (45.3 g, 0.5 mol) in dimethylformamide (300 ml) and the mixture was stirred at 80° C. for 3 hours under an argon atmosphere. The reaction mixture was poured into ice-cold water. Crystals precipitated were filtered, washed with water and dried. The crude crystals obtained were recrystallized from isopropyl ether to obtain the desired compound (80.0 g, yield: 71.6% ), m.p. 144°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cn1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine