Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH:3]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Br:20]N1C(=O)CCC1=O>ClCCl>[Br:20][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH:3]([CH:2]([CH3:1])[CH2:18][CH3:19])[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(C)C(C(=O)OC(C)(C)C)c1ccc(C)cc1
Solvent: ClCCl
Product: CCC(C)C(C(=O)OC(C)(C)C)c1ccc(CBr)cc1

Procedure:
15 g (59.1 mmol) of tert-butyl 3-methyl-2-(4-methylphenyl)pentanoate, 11 g (62 mmol) of N-bromosuccinimide and 97 mg (0.59 mmol) of 2,2′-azobis-2-methylpropionitrile in 150 ml of dichloromethane were stirred under reflux for 2 h. After the reaction had gone to completion, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 16.22 g (47.5 mmol, 80% of theory) of a colorless oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[CH3:32][NH:33][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=3[O:30][CH3:31])[C:15]=2[O:14]1
Reactant: CN
Reactant: COc1cccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1OC
Product: CNCC1Cc2cccc(-c3cccc(OC)c3OC)c2O1

Procedure:
The title compound was prepared (0.137 g, 63%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.283 g, 0.64 mmol) and methylamine (0.199 g, 6.42 mmol). mp 163-166° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]([OH:28])=[C:8]2[C:16]=1[Cl:17]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2Cc1ccc(OC)cc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2c(Cl)c(Cl)c3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 449 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[CH3:12][CH2:13][CH2:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18]>C1COCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:15]([OH:19])([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH3:12]
Reactant: Brc1cccs1
Reactant: CCCC(=O)CCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromothiophene (10.0 g, 61.5 mmol) in dry THF (60 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (2.5 M, 27.0 mL, 67.5 mmol) was then added slowly, and the resulting mixture was stirred at −78° C. for 2 hours, before a solution of 4-heptanone (8.5 g, 74.4 mmol) in dry THF (10 mL) was added slowly. This mixture was stirred at −78° C. for an additional 1 hour, and then allowed to warm to room temperature, and stirred at room temperature overnight. Most of the solvent was removed in vacuo, and the residue was subjected to flash column chromatography on silica gel with a hexane:EtOAc (3:1, v/v) mixture, leading to a colorless oil as the product (10.2 g, 83.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[CH2:36]([C:38]1([OH:42])[CH2:41][NH:40][CH2:39]1)[CH3:37].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:36]([C:38]1([OH:42])[CH2:41][N:40]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:28][CH:27]=2)[CH2:39]1)[CH3:37]
Reactant: CCC1(O)CNC1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccc(OC)cc5)o4)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a solution of 55A (0.20 g, 0.53 mmol) in DCM (10 mL) was added 70A (0.20 g, 0.93 mmol) followed by DIPEA (0.17 mL, 0.95 mmol). The mixture was stirred at RT for 20 min and then sodium triacetoxyborohydride (0.22 g, 1.05 mmol) was added. The mixture was stirred at RT overnight and then washed with an aqueous solution of Na2CO3. The organic solution was filtered through a phase separator and then the solvent was removed by evaporation. The product was purified on a silica gel column using ethyl acetate and then 5% methanol in DCM where the methanol contained 2M ammonia. There was obtained 128 mg (52%) of 70 as a solid. 1H NMR (500 MHz, CDCl3): δ 0.95 (t, 3H), 1.77 (q, 2H), 3.02 (d, 2H), 3.30 (d, 2H), 3.60 (s, 2H), 3.88 (s, 3H), 4.32 (m, 1H), 4.63 (m, 1H), 4.72 (m, 1H), 5.10 (m, 2H), 6.71 (d, 2H), 7.01 (d, 2H), 7.22 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 465 [M+H]+, LC purity: 97%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]([C:15]([F:21])([F:20])C(F)(F)F)=[N:4]1)C.[F:22]C(F)(F)C1C(C(F)(F)F)=C(C(OCC)=O)NN=1.IC>>[CH3:1][N:3]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:12])([F:13])[F:14])[C:5]([C:15]([F:20])([F:21])[F:22])=[N:4]1
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(F)(F)F
Reactant: CCn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Solvent: CI
Product: Cn1nc(C(F)(F)F)c(C(F)(F)F)c1C(=O)O

Procedure:
1-Methyl-3,4-bis(trifluoromethyl)-1H-pyrazole-5-carboxylic acid is synthesized analogously to the preparation of 1-ethyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid from ethyl 3,4-bis(trifluoromethyl)-1H-pyrazole-5-carboxylate and iodomethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18].O1CCCC1.CO.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18]
Reactant: COc1ccc(C=O)cc1OCc1nc(-c2ccccc2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CO)cc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (3.23 g), tetrahydrofuran (15 ml) and methanol (15 ml) was added sodium borohydride (0.378 g) at room temperature and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals of 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol. Recrystallization from tetrahydrofuran-hexane gave pale-yellow plate crystals (3.22 g, 99%). melting point: 144-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:10][C:11]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:5]=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][C:11]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cncc(Br)c2)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cncc(COCC2(c3ccccc3)CCNCC2)c1
Reaction time: 1 h
Yield: 112.4 %

Procedure:
A solution of tert-butyl 4-(((5-bromopryidin-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (100 mg, 0.2 mmoL) in methylene chloride (2 mL) was treated with TFA (0.5 mL). After 1 h, the reaction was concentrated, and the resulting residue was evaporated from methylene chloride (2×). Preparative HPLC afforded 88.0 mg (92%) of the desired compound as its TFA salt. 1H-NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H), 8.52 (s, 1H), 7.84 (s, 1H), 7.24-7.43 (m, 5H), 6.85 (s, br, 1H), 4.46 (s, 2H), 3.45 (s, 2H), 3.33-3.38 (m, 2H), 2.91-2.95 (m, 2H), 2.43-2.48 (m, 2H), 2.22-2.30 (m, 2H). Mass spec.: 362.99 (MH)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:29])=[C:5]([N:16]2[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]2)[S:6][C:7]=1[NH:8][C:9](=[O:15])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])#[N:2].FC(F)(F)C(O)=O.[Cl:37][C:38]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:39]=1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.ClC(Cl)C>[C:1]([C:3]1[C:4]([CH3:29])=[C:5]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:43]3[CH:42]=[CH:39][C:38]([Cl:37])=[CH:45][C:44]=3[Cl:46])[CH2:18][CH2:17]2)[S:6][C:7]=1[NH:8][C:9](=[O:15])[CH:10]([CH2:11][CH3:12])[CH2:13][CH3:14])#[N:2]
Reactant: CCC(CC)C(=O)Nc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1C#N
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCC(CC)C(=O)Nc1sc(N2CCN(Cc3ccc(Cl)cc3Cl)CC2)c(C)c1C#N

Procedure:
To a solution of 1.06 g (2.52 mmol) of the title compound from Example 30 in 10 mL of CH2Cl2 was added 10 mL of trifluoroacetic acid. After 2 h at ambient temperature the reaction was concentrated in vacuo. To 0.040 g (0.092 mmol) of this intermediate in 1 mL of dichloroethane was added 0.055 g (0.20 mmol) of 2,4-dichlorobenzaldehyde, followed by 0.066 g (0.31 mmol) of sodium triacetoxyborohydride. After 16 h at ambient temperature the reaction was quenched by the addition of 10 mL of saturated aqueous NaHCO3. The reaction was extracted with CH2Cl2 and the organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by preparative thin layer chromatography (15% EtOAc in hexane) afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3) 8.79 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.25 (dd, J=2.0 Hz, J=8.5 Hz, 1H), 3.64 (s, 2H), 2.94 (t, J=4.5 Hz, 4H), 2.63 (t, J=4.5 Hz, 4H), 2.28 (m, 1H), 2.16 (s, 3H), 1.73 (m, 2H), 1.61 (m, 2H), 0.95 (t, J=7.5 Hz, 6H); mass spectrum (ES) m/e=479.1 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([O:24]C)[CH:17]=2)/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:24])[CH:17]=2)/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2ccc(OC)c(OC)c2)C(=O)O)n1Cc1ccccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCc1ncc(/C=C(\Cc2ccc(O)c(O)c2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3,4-dimethoxyphenyl)methyl-2-propenoic acid, prepared in Example 28, was treated with boron tribromide in methylene chloride to give the title compound; mp 129-I33° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].CN(C=O)C.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>CCOC(C)=O>[Si:27]([O:1][CH2:2][C@@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
(R)-tert-butyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (21) (4.4 g, 17.5 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by DMF (35 mL) and cooled to 0° C. via an ice bath. Next, TBDMSCl (2.9 g, 19.3 mmol, 1.1 equiv.) and imidazole (2.4 g, 35.1 mmol, 2.0 equiv.) were added to the reaction flask. The solution was stirred at 0° C. for 1 h and then allowed to warm to rt, stirring an additional 2 h. The reaction solution was transferred to a 500 mL separatory funnel with EtOAc (150 mL). The mixture was washed with 1% HCl (3×40 mL), sat. NaHCO3 (1×40 mL), and sat. NaCl (2×40 mL). The organic layer was separated and dried over Na2SO4. The solution was concentrated on a rotary evaporator and dried under vacuum to give 5.9 g (93%) of 22 as a colorless oil. Rf=0.54 (50% EtOAc/hexanes); [α]D23.5=+3.55 (c 1.22, MeOH); IR (film) 3437, 3324, 2953, 2929, 2884, 2856, 1715, 1666, 1496, 1471, 1365, 1253, 1171, 1114 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.34 (br d, J=8.5 Hz, 1H, carbamate-NH), 4.73 (br s, 1H, Boc-NH—CH), 3.83 (m, 1H, CH—CH2), 3.77 (m, 1H, CH—CH2), 3.73 (s, 3H, N—OCH3), 3.19 (s, 3H, NCH3), 1.41 (s, 9H, Boc-t-butyl-CH3), 0.84 (s, 9H, Si-t-butyl-CH3), 0.00 (s, 6H, Si—(CH3)2); 13C NMR (125 MHz, CDCl3) δ 170.9, 155.5, 79.7, 63.6, 61.6, 52.6, 32.3, 28.5, 25.9, 18.4, −5.4; LRMS (ESI-MS m/z): Mass calcd for C16H34N2O5Si [M]+, 362.54. Found 363. Anal. calcd for C16H34N2O5Si: C, 53.01; H, 9.45; N, 7.73 Found: C, 53.26; H, 9.63; N, 7.68.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:18][O:19][CH2:20][CH3:21])[N:14]([CH2:15][CH2:16][CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[CH:5][C:4]=2[N:3]=1>Cl>[CH2:20]([O:19][CH2:18][C:13]1[N:14]([CH2:15][CH2:16][CH3:17])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:22][CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:21]
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Agent: Cl
Product: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Temperature: 65 °C
Yield: 87.4 %

Procedure:
tert-Butyl 4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate (2.45 g, 5.07 mmol) was taken up in 4.0M ethanolic hydrogen chloride (15 mL) and heated to 65° C. for 1 hour. The heat was removed and the reaction was allowed to cool to ambient temperature. The ethanol was removed under reduced pressure and the solid residue was dissolved in water (10 mL) and saturated aqueous sodium. chloride (10 mL). The solution was brought to pH 13 with 50% aqueous sodium hydroxide and then extracted with chloroform. The organic fraction was sequentially washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated. Trituration with acetonitrile, followed by filtration afforded 1.70 g of 2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid, mp 202-204° C.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Cl.Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(=O)(O)[O-]>O>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: Brc1ccncc1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccncc2)CCN(C)C1
Temperature: 99 °C
Yield: 110.6 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (138 mg, 0.6 mmol), 4-bromopyridinehydrochloride (100 mg, 0.51 mmol), dichlorobistriphenylphosphine palladium (II) (10 mg, 0.015 mmol) and TBAF.3H2O (481 mg, 1.5 mmol) was heated at 50° C. (observed exothermic temperature was 99° C.) for 5 min by microwave. After completion of reaction (monitored by TLC&LCMS), the mixture was poured into water (20 mL), saturated bicarbonate was added, and the mixture extracted with EtOAc (3×20 mL). The organic layer was washed with water (2×20 mL), dried over sodium sulfate and concentrated under vacuum to obtain 170 mg of 2,8-dimethyl-5-pyridin-4-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm): 8.58 (d, 2H), 7.42 (d, 1H), 7.34 (d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 3.62 (s, 2H), 3.08 (m, 2H0, 3.92 (m, 2H), 2.60 (s, 3H0, 2.42 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=2[O:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(#N)C.CC(C)=O>[C:23]([C:21]1[CH:20]=[CH:19][C:18]([O:25][C:26]2[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=2)=[C:17]([S:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH:7][C:5]([NH:4][CH2:3][CH2:2][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:6])[CH2:13][CH2:12]2)(=[O:15])=[O:16])[CH:22]=1)#[N:24]
Reactant: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(NC(=O)NCCCl)CC2)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(NC(=O)NCCN3CCOCC3)CC2)c1
Reaction time: 3 h
Yield: 65.5 %

Procedure:
1-(2-chloroethyl)-3-(1-(5-cyano-2-(3,5-dichlorophenoxy)-phenylsulfonyl)piperidin-4-yl)urea (838 mg), potassium carbonate (655 mg, 3.0 eq.) and morpholine (413 mg, 3.0 eq.) were dissolved in acetonitrile (25 mL) and heated to reflux. After three hours, the reaction was complete (confirmed by HPLC). The mixture was then concentrated in vacuo, the solid triturated with dichlormethane and isopropyl ether to obtain a white powder. The powder was suspended in hot acetone, cooled in an ice bath, filtered, and washed with water to obtain the product as a white powder (601 mg, 65% yield, 97% purity).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccc(C(F)(F)F)cc2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccc(C(F)(F)F)cc3)cc2=O)n1
Yield: 9 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-[6-oxo-4-(4-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 23) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(4-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a yellow solid (23.1 mg, 9%); ES+-HRMS m/e calcd for C26H30F3N5O4 [M+H+] 534.2323 found 534.2324. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.07 (m, 1H), 1.16-1.79 (m, 8H), 1.92 (m, 1H), 2.25 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.49 (dd, J=4.3, J=11.1 Hz, 1H), 6.01 (d, J=2.9 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.16 (d, J=2.9 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10](O)(=O)/[CH:11]=[CH:12]\[C:13](O)=O>C(O)C.C(OCC)(=O)C>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:3](=[N:2][CH2:10][C:11]1[CH:8]=[CH:7][CH:6]=[CH:13][CH:12]=1)[CH2:4][CH3:5]
Reactant: CNCc1ccccc1
Reactant: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(=NCc1ccccc1)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The oily ethoxyiminium salt was combined with 7.6 mL (59 mmol) of methylbenzylamine in 70 mL of ethanol and stirred at room temperature 24 hours. It was then heated for 2 hours at 90°, cooled to 0°, and the solid amidine was filtered off. The solid was dissolved in ethyl acetate and 1 equivalent of maleic acid in ethyl acetate was added to yield 5.1 g of product as the maleate salt, mp 116-118.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6](O)[C:7]3[CH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][C:11](=[O:17])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][C:11](=[O:17])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)c2c(n(O)c3ccc(Cl)cc3c2=O)C1
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: CC1(C)CC(=O)c2c([nH]c3ccc(Cl)cc3c2=O)C1
Yield: 74.2 %

Procedure:
20 g (0.066 mole) of 7-chloro-3,3-dimethyl-10-hydroxy-1-oxo-1,2,3,4-tetrahydro-9(10H)-acridone were suspended in 320 ml of chloroform and, after heating on a steam bath, combined dropwise with 11.3 ml (0.13 mole) of phosphorus trichloride. Upon cooling, 16 g of 7-chloro-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-9(10H)-acridone crystallized in the form of the hydrochloride. This compound was dissolved in a mixture of 300 ml of methanol and 50 ml of binormal sodium hydroxide solution, the solution was filtered, the filtrate was concentrated under reduced pressure and the base that had crystallized was filtered off with suction. 13.5 g (74 % ) of 7-chloro-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-9(10H)-acridone were obtained. Decomposition point 300° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[O:4][C:3]1=[O:9].[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([Cl:19])[CH:12]=1.ClC1C=C(NC(=O)C(C)CCC(O)=O)C=CC=1C#N>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Cl:19][C:13]1[CH:12]=[C:11]([NH:10][C:5](=[O:8])[CH2:6][CH2:7][CH:2]([CH3:1])[C:3]([OH:4])=[O:9])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: CC1CCC(=O)OC1=O
Agent: CC(CCC(=O)O)C(=O)Nc1ccc(C#N)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CCC(=O)Nc1ccc(C#N)c(Cl)c1)C(=O)O
Yield: 39 %

Procedure:
A solution of 3-methyldihydro-2H-pyran-2,6(3H)-dione (876 mg, 6.84 mmol), 4-amino-2-chlorobenzonitrile (1044 mg, 6.84 mmol) and TEA (0.953 mL, 6.84 mmol) in toluene (10 mL) was stirred at 70° C. for 3 hr. To the reaction mixture was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by COOH-silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give a mixture (750 mg, 2.67 mmol, 39.1%) of 5-((3-chloro-4-cyanophenyl)amino)-2-methyl-5-oxopentanoic acid and 5-((3-chloro-4-cyanophenyl)amino)-4-methyl-5-oxopentanoic acid, as a colorless powder.