Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][N:10]1[C:15]([C:16](Cl)=[O:17])=[C:14](N2CCCC2)[C:13]2[CH:24]=[CH:25][C:26]3[C:31]([C:12]=2[S:11]1(=[O:33])=[O:32])=[CH:30][CH:29]=[CH:28][CH:27]=3.CN1C=C(N2CCCC2)C2C=CC3C(C=2S1(=O)=[O:54])=CC=CC=3.C(Cl)(Cl)=O.C(N(CC)CC)C.Cl>O1CCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:16]([C:15]2[N:10]([CH3:9])[S:11](=[O:33])(=[O:32])[C:12]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:13]=3[C:14]=2[OH:54])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: CN1C(C(=O)Cl)=C(N2CCCC2)c2ccc3ccccc3c2S1(=O)=O
Reactant: Nc1cccc(Cl)c1
Reactant: CN1C=C(N2CCCC2)c2ccc3ccccc3c2S1(=O)=O
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1C(C(=O)Nc2cccc(Cl)c2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A solution of 0.51 gm (44 millimols) of 3-chloro-aniline in 8 ml of dry tetrahydrofuran was added dropwise to a solution of 2-methyl-4-(1-pyrrolidyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acidchloride-1,1-dioxide in tetrahydrofuran at -40° C. The latter solution was obtained by reacting 0.63 gm (2 millimols) of 2-methyl-4-(1-pyrrolidyl)-2H-naphtho[2,1-e]-1,2-thiazine-1,1-dioxide with 0.25 gm (2.5 millimols) of phosgene and 0.25 gm (2.5 millimols) of triethylamine in 16 ml of anhydrous tetrahydrofuran, as described below. The reaction mixture was allowed to warm to room temperature for 24 hours.Then, ice water was added, and the aqueous mixture was extracted twice withmethylene chloride. The combined organic phases were washed twice with water, dried over sodium sulfate and evaporated in vacuo. Petroleum ether was added to the residue, whereby crude crystalline N-(3-chloro-phenyl)-2-methyl-4-(1-pyrrolidyl)-2H-naphtho[2,1-e]-1,2 -thiazine-3-carboxamide-1,1-dioxide, m.p. 163°-167° C (decomp.), was obtained, which was immediately dissolved in 6 ml of aceticacid, and 2 N hydrochloric acid were added to the solution. The mixture washeated at 100° for 30 minutes, allowed to cool, and 50 ml of ice water were added. The precipitated product was filtered off, dried and recrystallized from ethylene chloride/petroleum ether, yielding 410 mgm (49% of theory) of N-(3-chloro-phenyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 247°-248° C (decomp.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([N:29]([CH3:30])[CH3:31])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: CN(C)C(=O)Cc1ccc(N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 32.9 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) and 2-(4-aminophenyl)-N,N-dimethylacetamide (0.178 g, 1.0 mmol) was heated for 3 h at 150° C., then toluene added and the mixture continued heating for an additional 7 h. After this time, the mixture was purified by silica gel chromatography eluting with methylene chloride and methanol. The resulting solid was converted to the HCl salt to afford the title compound (0.048 g, 33%) as a white solid. MW=405.92. 1H NMR (DMSO-d6, 500 MHz) δ 14.2 (br s, 1H), 9.88 (s, 1H), 7.91-7.90 (m, 1H), 7.72-7.66 (m, 2H), 7.61-7.58 (m, 1H), 7.37-7.32 (m, 1H), 7.01 (s, 1H), 3.73 (s, 2H), 3.17 (t, J=7.7 Hz, 2H), 3.04 (s, 3H), 2.93 (t, J=7.2 Hz, 2H), 2.84 (s, 3H), 2.27-2.21 (m, 2H); ESI MS m/z 406 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][NH:26][CH3:27])[C:12]3[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:32](N(CC)CC)C.C(Br)[CH:40]=[CH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][N:26]([CH3:32])[CH2:27][CH:40]=[CH:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:12]3[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CCOC(=O)CO[C@H]1C(=O)N(CCNC)c2ccccc2S[C@H]1c1ccc(OC)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CO[C@H]1C(=O)N(CCN(C)CC=Cc2ccccc2)c2ccccc2S[C@H]1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (+)-cis-2-(4-methoxyphenyl)-3-(ethoxycarbonylmethyl)oxy-5-[2-(methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (1.0 g), triethylamine (375 mg), cinnamyl bromide (730 mg) and methylene chloride (20 ml) is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent; chloroform: ethanol=20:1) to give (+)-cis-2-(4-methoxyphenyl)-3(ethoxycarbonylmethyl)oxy-5-[2-(N-methyl-N-cinnamylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one as oil product.
Reaction SMILES: C(OC(=O)CCC[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](I)[CH:25]=[C:24]([C:29]3[CH:37]=[CH:36][C:32]4[O:33][CH2:34][O:35][C:31]=4[CH:30]=3)[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])C.[N:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1>>[CH2:43]([O:42][C:40](=[O:41])[CH:39]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:49]3[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=3)[CH:25]=[C:24]([C:29]3[CH:37]=[CH:36][C:32]4[O:33][CH2:34][O:35][C:31]=4[CH:30]=3)[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH3:10])[CH3:44]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Product: CCOC(=O)CCc1c(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccc4c(c3)OCO4)c2)cccc1OC(CC)C(=O)OCC
Yield: 124.7 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-iodo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (87 mg, 0.12 mmol) and pyridin-4-ylboronic acid (45 mg, 0.36 mmol) to afford 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-pyridin-4-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy-butyric acid ethyl ester (51 mg, 63%) as a light yellow oil: ES(+)-HRMS m/e calculated for C41H47NO8 (M+H)+ 682.3375, found 682.3369.
Reaction SMILES: [C:1]1([C:7](O)([C:9]#[CH:10])C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1[CH:14]=[CH:15][C:16]([C:20]([OH:23])([CH3:22])[CH3:21])=[N+:17]([O-:19])[CH:18]=1.[CH:24]([NH:27][C:28]([C:30]1[C:39](=[O:40])[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32](C2C=CC=C(Br)C=2)[CH:31]=1)=[O:29])([CH3:26])[CH3:25]>>[CH:24]1([NH:27][C:28]([C:30]2[C:39](=[O:40])[C:38]3[C:33](=[N:34][CH:35]=[CH:36][CH:37]=3)[N:32]([C:5]3[CH:4]=[CH:3][CH:2]=[C:1]([C:7]#[C:9][C:10]4[CH:18]=[N+:17]([O-:19])[C:16]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=4)[CH:6]=3)[CH:31]=2)=[O:29])[CH2:25][CH2:26]1
Reactant: CC(C)(O)c1ccc(Br)c[n+]1[O-]
Reactant: C#CC(C)(O)c1ccccc1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Product: CC(C)(O)c1ccc(C#Cc2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)c[n+]1[O-]

Procedure:
Following the procedure of EXAMPLE 15, but substituting N-cyclopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 6 for 2-phenyl-3-butyn-2-ol and 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine-N-oxide from present Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the N-cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH3:31].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH2:28][N:29]([CH2:30][CH3:31])[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: CCNCCN
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CCN)C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, N-(2-aminoethyl)ethylamine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.82 minutes; C21H23Cl2N5O2 (448.35); mass spectrum: (M−H)−=447/449/451 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[C:17]1(C)[C:18]([S:23]([Cl:26])(=[O:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=C[CH:29]=1>>[ClH:26].[C:21]1([CH3:29])[CH:22]=[CH:17][C:18]([S:23]([N:14]2[CH2:15][CH2:16][C:3]3[C:4](=[N:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[CH3:1])[CH2:12][CH2:13]2)(=[O:24])=[O:25])=[CH:19][CH:20]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CCc3nc4ccccc4c(C)c3CC2)cc1
Product: Cl
Yield: 50 %

Procedure:
3-p-Toluenesulfonyl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline hydrochloride was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline with -toluenesulfonyl chloride in pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([O:27]C)=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C(Cl)(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([OH:27])=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCOC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@H]1COCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of (S)-methyl 2-(4-fluorophenyl)-3-(3-methylmorpholino)quinoxaline-6-carboxylate (140.0 mg, 0.37 mmol,) in methanol (15 mL) and CHCl3 (5 mL) was added a solution of NaOH (45 mg, 1.12 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(4-fluorophenyl)-3-(3-methylmorpholino)quinoxaline-6-carboxylic acid as a yellow solid (91.2 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=O)[N:13]=2)=[N:6][CH:7]=1.C1C=CC2N(O)N=[N:32][C:30]=2C=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.CN>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([NH:32][CH3:30])=[O:18])[N:13]=2)=[N:6][CH:7]=1
Reactant: O=C(O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
A mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.100 g, 0.238 mmol) (Example 315) HOBT-H2O (0.0547 g, 0.357 mmol), DIEA (d 0.742) (0.0870 mL, 0.500 mmol), EDCI (0.0684 g, 0.357 mmol), and methanamine (0.238 mL, 0.476 mmol) in 10 mL acetonitrile was stirred at ambient temperature for 5 hours and then heated at 50° C. overnight. The mixture was concentrated to a residue, dissolved in THF and precipitated with the addition of water. The solids were filtered, washed with water and dried on high vacuum overnight to give the title compound (0.072 g, 69.8% yield) as white solids. 1H NMR (d6 DMSO) δ 2.41 (t, J=7.8 Hz, 2H), 2.56 (d, J=4.7 Hz, 3H), 2.79 (t, J=7.7 Hz, 2H), 6.62 (s, 1H), 7.10 (d, J=8.0 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.43 (t, J=7.9 Hz, 2H), 7.77 (d, J=4.3 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 10.94 (br s, 1H).
Reaction SMILES: S(=O)(O)O.[CH:5]1([CH:11]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH2:11]([N:14]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CC1CCCCC1
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(O)O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of cyclohexanecarboxaldehyde bisulfite adduct (5.0 mmol) and Et3 N (5.5 mmol) in dichloroethane (20 mL) was stirred at room temperature for 15 min. The suspension was treated with N-methylbenzylamine (5.5 mmol) and was stirred for 45 min. NaBH(OAc)3 (7.0 mmol) was added portion-wise over approximately 30 min. After 16 h, the reaction mixture was diluted with EtOAc (80 mL), and was washed with 1 N NaOH (25 mL) followed by brine (25 mL). The organic layer was dried (MgSO4) and concentrated to yield benzyl-cyclohexylmethyl-methyl-amine as an oil. The crude material was purified by the General Purification Method as described above.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:25][CH:24]=1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccc(F)cc3)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 4-fluorophenylboronic acid (81 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh3)4 (17 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated to dryness, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 5-(2-(4-fluorophenyl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.3 (s, 1H), 7.17 (d, 1H), 7.02 (d, 1H), 6.8-6.98 (m, 4H), 4.7 (d, 1H), 4.3 (d, 1H), 3.65 (m, 1H), 3.41 (m, 1H), 2.9-3.18 (m, 7H), 2.52-2.77 (m, 2H), 2.45 (s, 3H), 2.21 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH2:33][N:34]4[CH2:39][C@H:38]([CH3:40])[O:37][C@H:36]([CH3:41])[CH2:35]4)[S:31][CH:32]=3)=[O:27])[C:13]3[C:17]([CH:18]=2)=[N:16][N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:14]=3)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].CN1CCOCC1.Cl[CH2:50][CH2:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[CH3:41][C@H:36]1[O:37][C@@H:38]([CH3:40])[CH2:39][N:34]([CH2:33][C:30]2[S:31][CH:32]=[C:28]([C:26]([NH:25][C:12]3[C:13]4[C:17]([CH:18]=[C:10]([C:4]5[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][S:52]([CH:51]=[CH2:50])(=[O:54])=[O:53])[CH:3]=5)[CH:11]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)=[O:27])[N:29]=2)[CH2:35]1
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn(C4CCCCO4)nc3c2)cc1N
Reactant: O=S(=O)(Cl)CCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn(C4CCCCO4)nc3c2)cnc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-[6-[5-Amino-6-(methyloxy)-3-pyridinyl]-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (250 mg) was dissolved in DCM (6 ml) and N-methylmorpholine (0.143 ml) was added. The reaction was cooled to 0° C. in an ice bath, then 2-chloroethanesulfonyl chloride (0.047 ml) was added dropwise. The reaction was left to warm to RT overnight. Reaction had blown dry, so was redissolved in DCM (6 ml). Further 2-chloroethanesulfonyl chloride (0.047 ml) was added and stirred at RT for 2 hours. Water (6 ml) was added to the reaction. The DCM was separated, passed through a hydrophobic frit, then evaporated to dryness to give crude title compound (250 mg) used directly in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:11][C:10]=2[C:36]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:37])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O.ClCCl>[NH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:10]([CH:11]=1)[C:36]([NH:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=[O:37]
Reactant: CC(C)(C)OC(=O)N(CCOCCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOCCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bis(1,1-dimethylethyl) (2-{[2-({4-[(phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}oxy)ethyl]oxy}ethyl)imidodicarbonate (may be prepared as described in Description 77; 340 mg, 0.56 mmol) was treated with trifluoroacetic acid/dichloromethane (v/v 40%, 10 ml). The mixture was stirred at 25° C. for 1 h. The solvent was removed under reduced pressure. The residue was purified twice by reverse phase HPLC using a gradient of acetonitrile and 0.1% aqueous ammonia as the eluent. Evaporation of the product-containing fractions yielded the title compound as a white solid. 86 mg.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+:20]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:14][CH2:15][C:16]([O-:18])=[O:17])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[Na+:20]
Reactant: CCCC(SCC(=O)O)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(SCC(=O)[O-])c1ccc2c(c1)OCO2

Procedure:
100 g of [{1-(1,3-benzodioxol-5-yl)butyl}thio] acetic acid was dissolved in 500 ml of ethanol. 372 ml of 1N-aqueous sodium hydroxide solution was added thereto. Ethanol and water were removed from the reaction mixture by azeotropic distillation and then ether was added to the residue to solidify it. A precipitate thus formed was recovered by filtration and dried to obtain 102 g of the intended compound in the form of a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:20][CH2:21][CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6](OCC)=[O:7])[CH3:2].[BH4-].[Li+].B(OC)(OC)OC>>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:20][CH2:21][CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[CH2:6][OH:7])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Li+]
Product: CCCC(NC(=O)Cc1ccc(CO)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)1-butyl}-aminocarbonylmethyl}-benzoate by reduction with lithium borohydride in boiling tetrathydrofuran in the presence of 10% of trimethyl borate.
Reaction SMILES: ClC1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])(O)[CH3:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:35]3[NH:39][C:38](=[O:40])[O:37][N:36]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.C(N(S(F)(F)[F:47])CC)C.Cl[CH2:51][Cl:52]>>[Cl:52][C:51]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([C:17]([F:47])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])[CH3:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:35]3[NH:39][C:38](=[O:40])[O:37][N:36]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(O)(c1ccccc1F)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: ClCCl
Reactant: CCN(CC)S(F)(F)F
Product: CC(F)(c1ccccc1F)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reaction time: 1 h

Procedure:
To a room temperature slurry of 3-{4-(5-chloropyridin-3-yl)-2-[1-(2-fluorophenyl)-1-hydroxyethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (38 mg, 0.067 mmol) in dichloromethane (1.35 mL) was added N,N-diethylaminosulfur trifluoride (0.045 mL, 0.337 mmol). The mixture was stirred for one hour, then quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic layers were washed with brine (1×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography (0-100% ethyl acetate/hexanes) to afford 3-{4-(5-chloropyridin-3-yl)-2-[1-fluoro-1-(2-fluorophenyl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one as a white solid. MS ESI calcd. for C29H27ClF2N6O2 [M+H]+ 565. found 565. 1H NMR (500 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.86 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 7.68-7.57 (m, 1H), 7.52-7.50 (m, 1H), 7.35-7.32 (m, 1H), 7.26-7.22 (m, 1H), 3.84-3.78 (m, 1H), 2.28 (d, J=23 Hz, 3H), 1.35-1.33 (m, 1H), 1.28-1.18 (m, 2H), 0.93-0.80 (m, 2H), 0.72-0.62 (m, 5H), 0.54-0.43 (m, 2H), 0.33-0.23 (m, 2H).