Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[CH2:9][N:10]([C:11]([N:13]3[CH2:19][CH2:18][CH2:17][N:16](C(OCC)=O)[CH2:15][CH2:14]3)=[O:12])[C:4]=2[CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[CH2:9][N:10]([C:11]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N1CCCNCC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 48.2 %

Procedure:
The title product of Example 59 (2.5 g, 5.8 mmol) was combined with 25 mL of concentrated HCl and 25 mL of dioxane. The solution was brought to reflux and maintained at reflux and under N2 for 6 days. After cooling the reaction to room temperature, all solvent was removed in vacuo and the residue was dissolved in EtOAc. This solution was brought to pH 8 with 2N NaOH and the organic solution was dried, filtered, and stripped of all solvent under reduced pressure. The residue was purified by chromatography to give 1.0 g of the title compound.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[S:12][C:13]([C:17]([O:19]CC)=O)=[C:14]([CH3:16])[N:15]=1>C(O)C>[CH3:16][C:14]1[N:15]=[C:11]([C:6]2[C:5]([O:4][CH3:3])=[CH:10][CH:9]=[CH:8][CH:7]=2)[S:12][C:13]=1[C:17]([NH:2][CH3:1])=[O:19]
Reactant: CCOC(=O)c1sc(-c2ccccc2OC)nc1C
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1sc(-c2ccccc2OC)nc1C
Yield: 72 %

Procedure:
Into a mixed solvent of 80 ml of 40% methylamine and 600 ml of ethanol, 13.9 g of ethyl 2-(2-methoxyphenyl)-4-methylthiazole-5-carboxylate was dissolved. Then, in a similar manner in Example 1, the object was obtained as colourless aciculate melting at 167.5° to 168.5° C. in an amount of 9.4 g corresponding to the yield of 72%.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]([OH:51])[CH:19]([C:23]3[C:32]4[C:27](=[C:28]([O:33][Si:34]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH:24]=3)[CH2:20][CH2:21]O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(OCC)(=O)C>O1CCCC1.O>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:19]([C:23]4[C:32]5[C:27](=[C:28]([O:33][Si:34]([C:47]([CH3:48])([CH3:50])[CH3:49])([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[C:41]6[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=6)[CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25][CH:24]=4)[CH2:20][CH2:21][O:51]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC=C2C(CCO)C(O)c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](Oc1cccc2c1CCC=C2C1CCOC1c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 68.4 %

Procedure:
To a solution of 1-[2-(4,5-diphenyloxazol-2-yl)-2-hydroxy-1-(2-hydroxyethyl)ethyl]-5-tert-butyldiphenylsilyloxy-3,4-dihydronaphthalene (1.5 g) in tetrahydrofuran (30 ml) were added triphenylphosphine (1.8 g) and diethyl azodiformate (1.2 ml) at room temperature. After being stirred for 12 hours at the same temperature, the mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-[2-(4,5-diphenyloxazol-2-yl)tetrahydrofuran-3-yl]-5-tert-butyldiphenylsilyloxy-3,4-dihydronaphthalene (1.0 g). MS (m/z): 674 (M+ +1) IR (Neat): 1580 cm-1NMR (CDCl3, δ): 1.07 (9H, s), 2.0-2.4 (3H, m), 2.6-3.1 (2H, m), 3.8-4.5 (4H, m), 5.47 (1H, d, J=8.0 Hz), 5.93 (1H, m), 6.39 (1H, d, J=8.0 Hz), 6.82 (1H, t, J=8.0 Hz), 7.02 (1H, d, J=8 Hz), 7.2-7.8 (10H, m)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])=[CH:24][CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:25]4[S:26][C:22]([C:20](=[O:21])[C:19]([F:18])([F:36])[F:37])=[CH:23][CH:24]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 5 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described in example 8 step 6 (8 mg, yield 5%). 1H NMR (400 MHz, DMSO-d6) δ 8.53-8.50 (t, J=6.2 Hz, 1H), 8.21 (m, 1H), 8.17-8.16 (m, 1H), 8.03-7.98 (m, 4H), 7.93-7.91 (m, 1H), 7.88-7.87 (d, J=4.3 Hz, 1H), 7.63-7.59 (t, J=7.8 Hz, 1H), 7.34-7.30 (t, J=8.8 Hz, 2H), 3.52-3.50 (d, J=6.4 Hz, 2H), 1.29 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].[N:35]1(C(OC(C)(C)C)=O)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.O1CCOCC1.Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@@H:31]([N:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3C)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@@H](N5CCNCC5)CC4)c3C)cc12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanone (12.0 mg, 0.0250 mmol), tert-butyl 1-piperazinecarboxylate (46.47 mg, 0.2495 mmol), sodium triacetoxyborohydride (10.58 mg, 0.04990 mmol) and 1,2-dichloroethane (3 mL, 40 mmol) was heated to 60° C. in a sealed tube for 1 h. The solution was extracted with DCM and sat. NaHCO3, and the organic layer was concentrated in vacuo. The material was dissolved in 1,4-dioxane (35 mL, 450 mmol), 4 M of HCl in 1,4-dioxane (1 mL, 4 mmol) was added, and the solution was allowed to stir at rt for 4 h. The material was concentrated in vacuo, loaded onto silica gel for column chromatography, and eluted with 5-10% (7N NH3 in MeOH)/DCM. The fractions containing the cis product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.59-1.77 (m, 4H), 1.82 (d, J=7.3 Hz, 3H), 2.16-2.36 (m, 8H), 2.57 (br. s., 4H), 2.95 (t, J=4.9 Hz, 4H), 3.66 (br. s., 3H), 4.28-4.38 (m, 1H), 5.12 (q, J=7.1 Hz, 1H), 6.90 (dd, J=9.1, 4.3 Hz, 1H), 7.10 (t, J=8.8 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.42 (s, 1H), 7.46 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). MS (ES+): m/z=551.27/553.27 (100/50) [MH+]. HPLC: tR=1.15 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(CCN)cc1
Product: COC(=O)c1ccc(CCN2CCCS2(=O)=O)cc1

Procedure:
Using methyl 4-(2-aminoethyl)benzoate (0.78 g) and 3-chloropropane-1-sulfonyl chloride (0.69 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (1.00 g) was obtained.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O-:11])=O.C(Cl)(=O)C(Cl)=O.[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Mg].C1(CCCCBr)C=CC=CC=1.[Mg].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[O:11]=[C:9]([CH2:30][CH2:29][CH2:28][CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:13][CH3:14])=[O:12]
Reactant: BrCCCCc1ccccc1
Reactant: COC(=O)CCCCCCCC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCCC(=O)CCCCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A commercially available reagent of monomethyl azelate (2.73 g, 13.5 mmol) was dissolved in toluene (21 mL), and N,N-dimethylformamide (0.00085 mL, 0.110 mmol) and oxalyl chloride (1.5 mL, 11.8 mmol) were then added. The reaction mixture was stirred at 60° C. for 2 hours, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (27 mL), and the solution was then cooled to −40° C. Iron (III) tris(acetylacetonate) (200 mg, 0.566 mmol) was added. Magnesium 4-phenylbutyl bromide, prepared beforehand, was then added dropwise over 10 minutes [Magnesium 4-phenylbutyl bromide was prepared as follows: 4-phenylbutyl bromide (2.96 g, 13.9 mmol) was dissolved in tetrahydrofuran (11 mL), and magnesium (337 mg, 13.9 mmol) was then added, and subsequently dissolved by stirring the mixture for 30 minutes with occasional warming by a dryer]. After 1.5 hours, ethyl acetate (100 mL) and a saturated aqueous solution (100 mL) of ammonium chloride were added. The outer temperature was then cooled to room temperature. After separation, the organic layer was washed with a saturated aqueous solution (100 mL) of sodium chloride. The solvent was then distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 1.81 g (5.68 mmol, 42% yield) of methyl 9-oxo-13-phenyl-tridecanoate.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:7]([O:9]C)=O)[N:2]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.F[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)NC2C=NC=CN=2)C1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[NH:18][C:7]([C@@H:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:9]
Reactant: COC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)OC(C)(C)C
Reactant: Nc1cnccn1
Agent: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)Nc2cnccn2)C[C@@H]2C[C@@H]21

Procedure:
(1S,3S,5S)-tert-Butyl 3-(pyrazin-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate 121B was prepared from 121A and 2-amino pyrazine using the procedure as reported in 65A. LC/MS [M+H]+: 305; Ret time (Method A): 1.63 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([C:40]#[N:41])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH:36]([C:40]#[N:41])[CH2:35]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: N#CC1CCCN(S(=O)(=O)c2ccccc2Br)C1
Product: N#CC1CCCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic 1-((2-bromophenyl)sulfonyl)piperidine-3-carbonitrile. MS (ESI): mass calcd. for C22H20FN5O2S, 437.13; m/z found, 438.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.29 (d, J=1.1, 1H), 8.11-8.07 (m, 1H), 7.98 (m, 1H), 7.74-7.68 (m, 1H), 7.65-7.60 (m, 1H), 7.44-7.40 (m, 1H), 7.36-7.30 (m, 2H), 3.06-3.02 (m, 2H), 2.90-2.86 (m, 2H), 2.80-2.74 (m, 1H), 1.89-1.80 (m, 1H), 1.77-1.61 (m, 2H), 1.53-1.42 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O([CH2:34][C:35]([F:38])([F:37])[F:36])S(C(F)(F)F)(=O)=O>C1COCC1.CN1C(=O)CCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][N:13]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:12](=[O:15])[CH2:11][CH2:10]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1CCC(c2cccc(F)c2F)CN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=C1CCC(c2cccc(F)c2F)CN1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-(2,3-difluorophenyl)piperidin-2-one (8.88 g, 42 mmol) in THF (250 mL) and NMP (170 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 48 mL, 48 mmol) over 5 min, keeping the internal temperature of the reaction mixture below 5° C. The resulting mixture was stirred at 0° C. for 15 min, then 2,2,2-trifluoroethyl triflate (11.2 g, 48 mmol) was added dropwise, keeping the internal temperature of the reaction mixture below 5° C. The reaction mixture was allowed to warm slowly to ambient temperature and stirring was continued for 3 h. The resulting mixture was partitioned between saturated aqueous sodium bicarbonate (800 mL) and EtOAc (1 L). The organic layer was removed and the aqueous phase was extracted further with EtOAc (500 mL). The combined organic extracts were washed with water, then brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=293.9 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[C:23]([O-:25])=[O:24])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:7]=1[C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(C(=O)[O-])n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)O)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Yield: 96.7 %

Procedure:
To a solution of 4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.40 g, 9 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) was added sodium hydroxide (1.08 g, 27 mmol). The obtained mixture was refluxed under heating for 3 h. The reaction mixture was pouted into water, and, after making the mixture acidic with 1N hydrochloric acid, extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (3.04 g, 96.8%) as crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1([C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18])[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH:9]1([C:14]2[N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:17]([CH3:18])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)CCC(=O)C1CCCC1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cn1c(C)ccc1C1CCCC1
Yield: 72.5 %

Procedure:
A slurry of ethyl 2-aminoacetate hydrochloride (2.93 g, 21.0 mmol), 1-cyclopentylpentane-1,4-dione (3.43 g, 20.4 mmol), and sodium bicarbonate (4.28 g, 51.0 mmol) in dichloromethane (20.4 mL) was heated at 50° C. for 72 hours, after which the reaction was diluted in water and extracted with dichloromethane (3×30 mL), dried (sodium sulfate), filtered and concentrated to a gold residue. Purification by silica gel chromatography (ISCO 120 g, 20 mL/min) using 0 to 35% ethyl acetate in hexanes afforded ethyl 2-(2-cyclopentyl-5-methyl-1H-pyrrol-1-yl)acetate (3.49 g, 14.8 mmol, 73% yield) as a clear colorless liquid. 1H NMR (400 MHz, CDCl3) δ (ppm): 5.84 (s, 2H, two shifts isochronous), 4.54 (s, 2H), 4.23 (q, 2H), 2.83 (m, 1H), 2.19 (s, 3H), 1.91-1.98 (m, 2H), 1.73-1.79 (m, 2H), 1.58-1.64 (m, 4H), 1.27 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1>[O-2].[Mn+4].[O-2].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cccc(C(O)c2cccnc2Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)c2cccnc2Cl)c1
Yield: 17.5 %

Procedure:
Combine (2-chloro-pyridin-3-yl)-(3-methoxy-phenyl)-methanol (9.40 g, 37.6 mmol), manganese (IV) oxide (30.0 g, 0.345 mol) and toluene (500 mL) and heat to reflux for one hour. Filter reaction mixture through celite, wash with toluene:dichloromethane mixture and evaporate to give the title compound (1.63 g, 66% Yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccnc(C)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-(4-(2-methylpyridin-4-yl)phenyl)acetate 26-2 (1.81 g, 7.1 mmol), LiOH (0.17 g, 7.1 mmol) in THF (30 mL), methanol (10 mL) and H2O (10 mL) was stirred at 60° C. for 1 hour. After cooled down to 0° C., the mixture was neutralized with 1 N HCl at 0° C. and then taken to dryness by rotary evaporation to yield 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 26-3. The product was used for next step without further purification. MS m/z 228.1 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][CH2:40][N:41]5[CH:45]=[N:44][N:43]=[CH:42]5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][CH2:40][N:41]5[CH:42]=[N:43][N:44]=[CH:45]5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCn4cnnc4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCn4cnnc4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.37 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:20→1:19), and was recrystallized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 155) (681.4 mg) as yellow crystals.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][C:8]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:29][C:28]([CH2:52][C:53]#[N:54])([N:30]4[CH:34]=[C:33]([C:35]5[C:36]6[CH:43]=[CH:42][N:41](COCC[Si](C)(C)C)[C:37]=6[N:38]=[CH:39][N:40]=5)[CH:32]=[N:31]4)[CH2:27]3)[CH2:22][CH2:21]2)=[O:19])[CH:9]=1.C(N(CC)CC)C.[CH3:62][CH:63]([NH2:65])[CH3:64]>C(Cl)Cl>[CH:63]([NH:65][CH2:7][C:8]1[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:29][C:28]([CH2:52][C:53]#[N:54])([N:30]4[CH:34]=[C:33]([C:35]5[C:36]6[CH:43]=[CH:42][NH:41][C:37]=6[N:38]=[CH:39][N:40]=5)[CH:32]=[N:31]4)[CH2:27]3)[CH2:24][CH2:25]2)=[O:19])[CH:9]=1)([CH3:64])[CH3:62]
Reactant: CC(C)N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NCc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
Methanesulfonyl chloride (2.8 0.036 mmol) in methylene chloride (0.20 mL) was added to a mixture of {1-(1-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (21 mg, 0.030 mmol, prepared as in Example 376, Step E) and triethylamine (8.4 μL, 0.060 mmol) in methylene chloride (1.0 mL) at 0° C. After 15 minutes, 2-propanamine (20 μL, 0.3 mmol) was added. The mixture was then heated to 40° C. After 1.5 hours, additional 2-Propanamine (20 μL, 0.3 mmol, Aldrich) was added and the reaction heated for a total of 3 hours at this temperature. The mixture was concentrated in vacuo. The residue was stirred for 1 hour in a 1:1 mixture of TFA/DCM, then concentrated again. The residue was redissolved in MeOH (1.0 mL) and ethylenediamine (0.2 mL) was added. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: 11.6 mg (63%); LC-MS: 608.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.15 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.97 (s, 1H), 7.61 (d, 1H), 7.07 (d, 1H), 41.2-4.02 (m, 1H), 3.94 (s, 2H), 3.75 (dd, 2H), 3.63-3.45 (m, 5H), 3.31-3.22 (m, 1H), 3.16-3.06 (m, 1H), 2.75 (septet, 1H), 2.61-2.53 (m, 1H), 1.84-1.75 (m, 1H), 1.70-1.60 (m, 1H), 1.36-1.19 (m, 2H), 1.01 (d, 6H). 19F NMR (400 MHz, DMSO-d6): δ −69.46 (s, 3F).