Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:36][CH2:35][CH2:34][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: NCCN1CCOCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCN3CCOCC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23, (586 mg; 1.41 mmol; 1 eq) is dissolved in anhydrous DCM (15 ml). The reaction is put under nitrogen. Then triethylamine (1.96 ml; 14.1 mmol; 10 eq) and 2-morpholin-4-yl-ethylamine (367 mg; 2.82 mmol; 2 eq) are added successively and the reaction mixture is stirred at room temperature for 30 minutes. Solvents are evaporated and the resulting crude product is purified by preparative HPLC, affording the title compound (100 mg; 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH3:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](=[O:31])[CH2:29]Br>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:29]=1[C:28](=[O:31])[C:27]1[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=1[O:25][CH3:24]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: COc1ccccc1C(=O)CBr
Product: COC(=O)Cc1c(C(=O)c2ccccc2OC)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-methoxyphenacyl bromide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=1[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][CH:23]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:24]1=[O:25]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]2[C:10]=1[C:18](=[O:20])[N:22]([CH:23]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:24]1=[O:25])[C:12]2=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccccc4)c3C2=O)C(=O)N1
Yield: 113.9 %

Procedure:
A mixture of 3-benzyloxy-phthalic acid (1.08 g, 4.00 mmol) and rac-α-aminoglutarimide hydrochloride (0.65 g, 4.0 mmol) in pyridine (10 mL) was heated to reflux for 4 h. The reaction mixture was cooled and the solvent was evaporated under vacuum. The residue was suspended in ethyl acetate (200 mL) and washed with dilute aqueous HCl (100 mL). The organic phase was combined with the insoluble precipitate and evaporated to dryness. The resulting solid was triturated with ethyl acetate (100 mL), filtered, washed with additional ethyl acetate (50 mL), and dried to give the title compound (1.66 g, 86% yield); mp 238-240° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.23 (96.71%); 1H NMR (DMSO-d6) δ 1.99-2.08 (m, 1H), 2.45-2.62 (m, 2H), 2.81-2.94 (m, 1H), 5.10 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 5.38 (s, 2H), 7.32-7.53 (m, 6H), 7.60 (d, J=8.5 Hz, 1H), 7.83 (t, J=8.2 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 48.8, 70.0, 115.6, 116.6, 120.2, 127.3, 128.0, 128.5, 133.3, 136.2, 137.0, 155.5, 165.3, 166.8, 169.9, 172.8; Anal. Calcd for C20H16N2O5: C, 65.93; H, 4.43; N, 7.69. Found: C, 65.54; H, 4.35; N, 7.63.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:13]1[N:14]([CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:11]([C:13]1[N:14]([CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:12]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1nc2cnc3ccccc3c2n1CCCC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere, dimethylsulfoxide (3.6 mL, 1.5 eq.) and oxalyl chloride (3.5 mL, 1.1 eq.) were sequentially added dropwise to chilled (dry ice/acetone bath) dichloromethane (100 mL). A solution of 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (10 g, 37 mmol, 1 eq.) in dichloromethane was added dropwise. Triethylamine (15.5 mL, 3 eq.) was added. The ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. After about 2 hours analysis by TLC indicated that the reaction was complete. The reaction mixture was diluted with dichloromethane (175 mL) and water (200 mL) and made basic (pH 10) with aqueous 5% sodium carbonate. The organic layer was washed sequentially with water (2×200 mL) and brine (150 mL) and then concentrated under reduced pressure to provide 9.9 g of 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butanal.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[C:3]1=[O:15].[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[C:3]1=[O:15]
Reactant: Cn1cccc(C2CCC(=O)CC2)c1=O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cn1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1=O

Procedure:
The title compound was prepared as a white solid from the reductive amination of 1-methyl-3-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: IF.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][N:5]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:11])=[O:20])=[CH:6][N:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Cl)nc1
Agent: FI
Product: CS(=O)c1ccc(Cl)nc1

Procedure:
2-Chloro-5-methylsulfinylpyridine was prepared by the method described in Example I-F from 2-chloro-5-methylthiopyridine using mCPBA as oxidant.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.I[CH3:30]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5[CH3:30])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1c(C(C)(C)C)[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc12

Procedure:
A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (75 mg, 0.20 mmol) and iodomethane (125 μL, 2.0 mmol) in N,N-dimethylformamide (1 mL) was heated at 120° C. in a sealed tube for 24 h. The reaction was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 390.5, found 391.3(M+1)+; retention time 2.04 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 10.30(s, 1H), 8.39(s, 1H), 7.51 (m, 1H), 7.13-7.11(m, 1H), 7.03-6.90(m, 4H), 6.03(s, 2H), 2.25(s, 3H), 1.40-1.38(m, 11H), 1.03-1.01(m, 2H).
Reaction SMILES: C[O-].[Na+].[Cl-].[CH3:5][O:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:27][C:28]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O>C(O)C>[CH3:5][O:6][CH:7]=[CH:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:35]([Cl:36])[C:28]=1[Cl:27]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COC=Cc1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
47.3 g of sodium methylate are introduced into 1.5 liters of absolute ethanol. There are then added portionwise, at room temperature, firstly 300.0 g of methoxymethyltriphenylphosphonium chloride and afterwards 142.5 g of 2,3-dichlorobenzaldehyde, and the reaction mixture is heated at 70° C. for about 60 hours. After cooling to room temperature, the mixture is filtered, and the filtrate is concentrated in vacuo. The residue is taken up in pentane, washed, again concentrated by evaporation, and filtered over SiO2 with dichloromethane. Excess solvent is removed in vacuo. There is thus obtained β-methoxy-2,3-dichlorostyrene as a 1:1 (E/Z) mixture in the form of a light-yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)CC)(C)C.[NH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[C:38]1([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:30][C:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:8])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1c[nH]cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Temperature: 35 °C
Reaction time: 48 h

Procedure:
A mixture of 11.7 g of 4-imidazolecarboxylic acid, 18.7 g of 1,1'-carbonyldiimidazole, 20 ml of diisopropylethylamine and 600 ml of DMF was heated at 35° C. for approximately 18 hours. Twenty milliters of aminodiphenylmethane were added and the solution stirred at 35° C. for approximately 21/2 days. The mixture was concentrated in vacuo and the residue added to 400 ml of water. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Two crystallizations from hot ethyl acetate/hexane provided 11 grams of the desired titled intermediate, m.p. 201°-202° C.
Reaction SMILES: O=C1C2NC(C(OC)=O)=CC=2CC1.BrC1C=C(C=CC=1)C[Mg]Br.[Br:24][C:25]1[CH:26]=[C:27]([CH:42]=[CH:43][CH:44]=1)[CH2:28][C:29]1(O)[C:33]2[NH:34][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:36][C:32]=2[CH2:31][CH2:30]1>O=[Pt]=O.CO>[Br:24][C:25]1[CH:26]=[C:27]([CH:42]=[CH:43][CH:44]=1)[CH2:28][CH:29]1[C:33]2[NH:34][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:36][C:32]=2[CH2:31][CH2:30]1
Reactant: COC(=O)c1cc2c([nH]1)C(O)(Cc1cccc(Br)c1)CC2
Agent: O=[Pt]=O
Agent: Br[Mg]Cc1cccc(Br)c1
Agent: COC(=O)c1cc2c([nH]1)C(=O)CC2
Solvent: CO
Product: COC(=O)c1cc2c([nH]1)C(Cc1cccc(Br)c1)CC2
Yield: 60 %

Procedure:
The title compound was synthesized in two steps. First, methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.502 g, 1.0 mmol) was reacted with 3-bromobenzylmagnesium bromide (28 mL, 2.5 mmol) according to General Procedure 3 to give the carbinol-containing compound methyl 6-(3-bromobenzyl)-6-hydroxy-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation with PtO2 (0.045 g, 0.20 mmol) according to General Procedure 6, and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane affording the title compound as a slightly yellow solid: 0.257 g (60% yield). 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.08-2.13 (m, 1H), 2.37-2.47 (m, 3H), 2.71 (dd, J1=13.47 Hz, J2=8.98 Hz, 1H), 3.19 (dd, J1=13.47 Hz, J2=4.69 Hz, 1H), 3.36-3.42 (m, 1H), 3.74 (s, 3H), 6.53 (d, J=1.9 Hz, 1H), 7.18-7.26 (m, 2H), 7.37-7.39 (m, 2H), 10.50 (s, 1H); LCMS-MS (ESI−) 332.0 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([CH:13]2[CH2:15][CH2:14]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C2CC2)cnc1N
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a suspension of 3-amino-6-bromopyrazine-2-carboxylic acid methyl ester (17.8 g, 76.7 mmol), cyclopropylboronic acid (8.57 g, 99.7 mmol), potassium phosphate (57.0 g, 268 mmol) and tricyclohexylphosphine (2.15 g, 7.67 mmol) in toluene (445 ml) and water (22 ml) was added palladium(II) acetate (0.86 g, 3.84 mmol). The reaction mixture was heated to 100° C. and stirred for 20 h. Water (200 ml) was added, the organic layer was washed with water and brine and the aqueous layer was back-extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as yellow solid (1.69 g, 11.4%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][C:26]([N:29](S(C)(=O)=O)[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])=[CH:27][CH:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CS(=O)(=O)N(c1ccc(Br)cc1)S(C)(=O)=O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(NS(C)(=O)=O)cc3)s2)c(F)c1

Procedure:
5-[2,6-difluoro-4-(1-hydroxy-1-methyl ethyl)phenyl]-2-({4-[(methylsulfonyl)amino]phenyl}amino)thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (85 mg, 0.272 mmol) and N-(4-bromophenyl)-N-(methylsulfonyl)methanesulfonamide (89 mg, 0.272 mmol) as the starting materials.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH:12]=O)[N:5]2[N:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH2:12][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]2[N:4]=1
Reactant: CSc1ncc2ccc(C=O)n2n1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1ncc2ccc(CNc3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (0.200 g, 1.04 mmol) and Aniline (0.104 mL, 1.14 mmol) were dissolved in a solution of Acetic acid (0.100 mL, 1.76 mmol) and Methylene chloride (10 mL, 200 mmol) and the reaction was allowed to stir at room temperature for 1 hour. Sodium triacetoxyborohydride (0.439 g, 2.07 mmol) was then added and the reaction was allowed to continue stirring at room temperature until HPLC showed consumption of starting material. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was then purified by Isco flash column chromatography (hexanes/ethyl acetate eluent) and combined fractions were reduced and dried under vacuum to afford 0.280 g of (2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-phenyl-amine. 1H NMR (400 MHz, DMSO, d6) δ 8.92 (s, 1H), 7.06 (m, 2H), 6.90 (d, 1H, J=4.61 Hz), 6.83 (d, 1H, J=4.61 Hz), 6.65 (m, 2H), 6.54 (t, 1H, J=7.28 Hz), 6.13 (t, 1H, J=6.16 Hz), 4.61 (d, 2H, J=6.16 hz), 2.56 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1.[CH3:16]I>C(#N)C.[Ag]=O>[CH3:16][O:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1
Reactant: COC(=O)c1ccc2[nH]cc(CO)c2c1
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COCc1c[nH]c2ccc(C(=O)OC)cc12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A 327 mg portion of methyl 3-(hydroxymethyl)-1H-indole-5-carboxylate was dissolved in 9 ml of acetonitrile, mixed with 385 mg of silver oxide and 3.6 ml of methyl iodide and stirred at 80° C. for 5 hours. A 385 mg portion of silver oxide was further added thereto and stirred overnight at 80° C. A 385 mg portion of silver oxide and 3.6 ml of methyl iodide were further added thereto and stirred at 80° C. for 9 hours. After cooling to room temperature, the insoluble matter was removed, the solvent was evaporated, and then the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6 to 1:5 to 1:4) to obtain 143 mg of methyl 3-(methoxymethyl)-1H-indole-5-carboxylate as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:15]3[C:14](=[O:22])[CH:13]=[CH:12][N:11]([CH3:23])[C:10]=3[C:9]2=[O:24])=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.O>[Br:27][C:13]1[C:14](=[O:22])[C:15]2[C:16]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:26][CH:25]=3)[C:9](=[O:24])[C:10]=2[N:11]([CH3:23])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CN2C(=O)c3c(c(=O)ccn3C)C23CCCCC3)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(CN2C(=O)c3c(c(=O)c(Br)cn3C)C23CCCCC3)cc1
Temperature: 90 °C

Procedure:
To a solution of 6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione (1.0 mmol, 1 eq) in carbon tetrachloride (25 mL), add N-bromosuccinimide and heat the mixture at 90° C. for 16 h. After completion the mixture was diluted with water and extracted with ethyl acetate. Remove the solvent under reduced pressure to get the crude. Purify the crude by column chromatography to afford 3′-bromo-6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione (7).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(OC([NH:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([OH:48])=[O:47])=O)(C)(C)C>>[C:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:25])[NH:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([OH:48])=[O:47])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCC(=O)ON1C(=O)CCC1=O
Product: CC(C)(C)OC(=O)CCCCCCCCC(=O)NCCOCCOCCNC(=O)CCC(=O)O
Yield: 121.1 %

Procedure:
Preparation from decanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (1.13 g, 3.45 mmol) and N-{2-[2-(2-tert-butoxycarbonylamino-ethoxy)-ethoxy]-ethyl}-succinamic acid (1 g, 2.84 mmol) as described in step 3 example 8 gave 1.68 g crude product which was used without further purification. LCMS (Method 6): Rt 3.86 min; m/z (M+1) 489; Calcd.: 489.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:2]=1>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCOCC#Cc1cccnc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOCCCc1cccnc1
Yield: 92.5 %

Procedure:
Under a nitrogen purge, 10% palladium on carbon (5.0 g) and 2-propanol (20 mL) were added to a pressure vessel. A solution of tert-butyl {2-[3-(pyridin-3-yl)prop-2-ynyloxy]ethyl}carbamate (22.7 g, 82.1 mmol) in methanol (200 mL) were then added. The vessel was purged three times with nitrogen and then placed under hydrogen pressure (50 psi, 3.4×105 Pa) for five hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to yield 21.3 g of tert-butyl {2-[3-(pyridin-3-yl)propoxy]ethyl}carbamate as a brown oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:34][C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)([C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].C(N(C(C)C)CC)(C)C>ClCCCl>[CH:19]1([NH:18][C:17]([C:14]2([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:41](=[O:43])[CH3:42])=[CH:29][CH:28]=3)[CH2:13][CH2:12][N:11]([C:9](=[O:10])[C@@H:8]([NH2:7])[CH2:34][C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)[CH2:16][CH2:15]2)=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)N1CCC(Cc2ccc(N)cc2)(C(=O)NC2CCCCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)[C@@H](N)Cc3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {2-[4-(4-aminobenzyl)-4-cyclohexylcarbamoyl-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester (0.352 mmol; 0.2 g) in 1,2-dichloroethane (5 mL) was added acetic anhydride (0.422 mmol; 0.043 g) and N,N-diisopropyl-N-ethylamine (0.703 mmol; 0.123 mL) and the resulting solution was stirred for 3 hours at room temperature. The resulting mixture was then evaporated and the residue was purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The resulting residue was dissolved in tetrahydrofuran (10 mL) and a 4N HCl in 1,4-dioxane solution (15 mL), and the mixture was then stirred for 6 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 4-(4-acetylaminobenzyl)-1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-piperidine-4-carboxylic acid cyclohexylamide as a hydrochloride salt.
Reaction SMILES: [O:1]=[O+][O-].[Cl:4][C:5]1[CH:6]=[C:7]([CH3:26])[C:8]2[NH:9][C:10](=[O:25])[C:11]3[CH:21]=[C:20]([CH2:22][CH:23]=C)[CH:19]=[N:18][C:12]=3[N:13]([CH2:16][CH3:17])[C:14]=2[N:15]=1.[BH4-].[Na+].[NH4+].[Cl-]>C(Cl)Cl.CO>[Cl:4][C:5]1[CH:6]=[C:7]([CH3:26])[C:8]2[NH:9][C:10](=[O:25])[C:11]3[CH:21]=[C:20]([CH2:22][CH2:23][OH:1])[CH:19]=[N:18][C:12]=3[N:13]([CH2:16][CH3:17])[C:14]=2[N:15]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1cnc2c(c1)C(=O)Nc1c(C)cc(Cl)nc1N2CC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CCN1c2ncc(CCO)cc2C(=O)Nc2c(C)cc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A stream of O3 was introduced into a cold (−78° C.) solution of 2-chloro-5,11-dihydro-11-ethyl-4-methyl-8-(2-propenyl)-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (8.04 g, 24.4 mmol) and Sudan III in CH2Cl2 (120 mL) and MeOH (120 mL). When the pink solution turned brown, O2 was bubbled through the solution for 10 min. NaBH4 (1.12 g, 29.4 mmol) was then added and the solution was allowed to warm to room temperature. After 30 min, an additional amount of NaBH4 (500 mg) was added. After 1 h, aqueous saturated NH4Cl was then added and the mixture stirred for 20 min. The solution was concentrated under reduced pressure and extracted with CH2Cl2 (3×). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (CHCl3:EtOH, 97:3) to give the title compound (6.01 g, 74% yield) as a white solid.