Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30](B2OC(C)(C)C(C)(C)O2)[C:29]([CH3:42])=[N:28]1>CN(C=O)C>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:30]1[C:29]([CH3:42])=[N:28][N:27]([CH3:26])[C:31]=1[CH3:32])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: Cc1nn(C)c(C)c1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (CAS RN 844891-04-9) and using DMF as reaction solvent. Pale yellow sticky liquid (11%). MS (ESI): m/z=457.6 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14](=[O:15])[N:13]3[CH2:16][CH2:17][N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:32]=[C:33]([I:35])[S:34][C:27]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14](=[O:15])[N:13]3[CH2:16][CH2:17][N:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[CH:32]=[C:33]([I:35])[S:34][C:27]=12
Reactant: O=c1c(-c2ccc(O)c(F)c2)cnc2n1CCN2c1ccccc1
Reactant: Clc1ccnc2cc(I)sc12
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: O=c1c(-c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)cnc2n1CCN2c1ccccc1

Procedure:
A mixture of 6-(3-fluoro-4-hydroxyphenyl)-1-phenyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (0.078 g, 0.186 mmol), 7-chloro-2-iodothieno[3,2-b]pyridine (0.050 g, 0.169 mmol; prepared according to the procedure of Ragan, J. A. Org. Proc. Res. 2003, 7, 676) and DMAP (0.021 g, 0.169 mmol) in bromobenzene (1.5 mL) under nitrogen was stirred at 150° C. for two days. The reaction was concentrated in vacuo to remove as much bromobenzene as possible and then purified directly by flash column chromatography, eluting with 30:1 CH2Cl2/MeOH. The product was obtained (35 mg; 36%) as a yellow solid. LRMS (APCI pos) m/e 583 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[F:15][C:16]([F:33])([F:32])[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26](=O)[C:27](OC)=[O:28].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:32][C:16]([F:15])([F:33])[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26]1[C:27](=[O:28])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(C(F)(F)F)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(C(F)(F)F)cc45)C(=O)NC3=O)c21
Temperature: 50 °C
Yield: 34.9 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (208 mg, 1.1 mmol) and methyl 2-(5-trifluoromethyl-1H-indol-3-yl)oxoacetate (300 mg, 1.1 mmol) in DMF (5.4 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.1 mL, 1.1 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional KOtBu (2.2 mL, 2.2 mmol) was added. The resulting dark red solution was heated up to 50° C. over night. The mixture was cooled to room temperature and quenched with 1 N HCl (9 mL) and poured into EtOAc (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (150 mL), and brine (3×150 mL). The solution was dried (MgSO4), filtered, and concentrated to a red solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (157 mg, 35%) as a red solid, mp 270–280° C. dec. 1H NMR (DMSO-d6) δ 12.24 (s, 1H), 11.26 (s, 1H), 8.11 (s, 1H), 7.63 (m, 1H), 7.55 (m, 1H), 7.27 (m, 2H), 6.92 (m, 2H), 6.65 (s, 1H), 6.49 (s, 1H), 3.73 (s, 3H). MS (ESI): m/z=411 [C22H14F3N3O2+H]+
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[H-].[Na+].I[CH3:32]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][O:27][CH3:32])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CI
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CO)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Reaction time: 0.17 h

Procedure:
To a solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one (0.35 g, 0.00078 mol) in DMF at 0° C., was added NaH (0.022 g, 0.00092 mol) and stirred for 10 min. Iodomethane (0.05 mL) was added to the reaction and the mixture was stirred at 10° C. for 3 h. DMF was distilled in vacuo and the residue was partitioned between 5% citric acid and EtOAc (15.0 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness. The residue was purified by flash chromatography (EtOAc), and the appropriate fractions were combined and concentrated to a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:35]([F:38])([F:37])[F:36])[CH:6]=[C:7]([NH:9][C:10](=[O:34])[N:11]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:12])[CH:8]=1.C([O-])(O)=O.[Na+].C(Cl)[Cl:45]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:35]([F:37])([F:38])[F:36])[CH:6]=[C:7]([NH:9][C:10](=[O:34])[N:11]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)=[C:22]([Cl:45])[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:12])[CH:8]=1
Reactant: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4cc(OC)cc(C(F)(F)F)c4)ncn3)cc2)CC1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4cc(OC)cc(C(F)(F)F)c4)ncn3)cc2Cl)CC1
Temperature: 0 °C

Procedure:
Portions of 0.4 mL of a 1 M solution of SO2Cl2 in DCM are added repeatedly over a period of 27 h to an ice-cooled suspension of 3-(5-methoxy-3-trifluoromethyl-phenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (105 mg, 0.20 mmol) (Example 26) in acetonitrile (6 mL). The reaction is followed by HPLC analysis. The reaction mixture (still containing starting material) is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with brine, dried (Na2SO4), filtered and concentrated. Reversed phase MPLC (H2O/CH3CN+0.1% TFA) yields, after neutralization of the product containing fractions with NaHCO3, partial concentration and extraction with DCM, the title compound: API-MS: 564/566 [MH]+; TLC: Rf=0.28 (DCM/MeOH+1% NH3aq, 95:5); 1H-NMR (DMSO-d6) δ 1.02 (t, H3C), 2.37 (q, H2C), 2.51 (m, 4H), 2.92 (m, 4H), 3.33 (s, H3C), 3.82 (s, H3C), 6.48 (s, 1H), 6.90 (s, 1H), 7.12 (d, 1H), 7.43 (m, 2H), 7.59 (s, 1H), 7.82 (s, 1H), 8.55 (s, 1H), 9.66 (s, HN), 12.33 (s, HN).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:39]=[CH:40][CH:41]=1)[CH2:20][O:21]/[N:22]=[C:23](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29].CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:39]=[CH:40][CH:41]=1)[CH2:20][O:21]/[N:22]=[C:23](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)CCCC/C(=N\OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CO/N=C(\CCCCC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-6-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoic acid (432 mg, yield 88%) as colorless crystals. m.p. 114-115° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](SC)=[N:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1.Cl.[NH2:20][OH:21].C(N(CC)C(C)C)(C)C>C(O)C>[NH2:1][C:2]1[C:3]([C:7](=[N:20][OH:21])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1
Reactant: NO
Reactant: CSC(=Nc1ccc(F)c(Br)c1)c1nsnc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nsnc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
A solution of methyl 4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carbimidothioate (78 mg, 0.22 mmol) in ethanol (2.3 mL) was treated with hydroxylamine hydrochloride (62 mg, 0.9 mmol) followed by N,N-diisopropylethylamine (180 μL, 1.0 mmol) and stirred at 90° C. for 16 h. The reaction mixture was purified by preparative HPLC to give the desired product (58 mg, 78%). LCMS for C9H8BrFN5OS (M+H)+: m/z=331.9, 333.9.
Reaction SMILES: ClC1C=C(NC2N(C)C(COC3[CH:18]=[C:19]4C(=CC=3)N[C:22](=[O:27])[CH:21]=[CH:20]4)=NN=2)C=CC=1Cl.[NH:29]1[C:37]2[C:32](=[CH:33][C:34]([CH2:38][CH2:39][C:40]3[N:41]([CH3:56])[C:42]([NH:45][C:46]4[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[CH:48][CH:47]=4)=[N:43][N:44]=3)=[CH:35][CH:36]=2)[CH:31]=[N:30]1>>[F:55][CH:53]([F:54])[O:52][C:49]1[CH:50]=[CH:51][C:46]([NH:45][C:42]2[N:41]([CH3:56])[C:40]([CH2:39][CH2:38][C:34]3[CH:33]=[C:32]4[C:37](=[CH:36][CH:35]=3)[N:29]([CH:22]3[CH2:21][CH2:20][CH2:19][CH2:18][O:27]3)[N:30]=[CH:31]4)=[N:44][N:43]=2)=[CH:47][CH:48]=1
Reactant: Cn1c(COc2ccc3[nH]c(=O)ccc3c2)nnc1Nc1ccc(Cl)c(Cl)c1
Reactant: Cn1c(CCc2ccc3[nH]ncc3c2)nnc1Nc1ccc(OC(F)F)cc1
Product: Cn1c(CCc2ccc3c(cnn3C3CCCCO3)c2)nnc1Nc1ccc(OC(F)F)cc1

Procedure:
By a procedure analogous to the synthesis of 6-((5-(3,4-dichlorophenylamino)-4-methyl-4H-1,2,4-triazol-3-yl)methoxy)quinolin-2(1H)-one (Example 276), 5-(2-(1H-indazol-5-yl)ethyl)-N-(4-(difluoromethoxy)phenyl)-4-methyl-4H-1,2,4-triazol-3-amine (0.131 g, 16%) was synthesized as an off-white gum. LCMS: RT 1.858 min; LCMS (ES-API), m/z 469 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:5][C@@H:4]([CH3:17])[O:3]1.[H][H]>CCO.[Pd]>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5][C@@H:4]([CH3:17])[O:3]1
Reactant: [H][H]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)O1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CN(c2ccc(N)cc2)C[C@H](C)O1

Procedure:
1-(Cis-2,6-dimethylmorpholino)-4-nitrobenzene (Method 18, 8 g) in EtOH (100 ml) was reduced with hydrogen over 10% palladium/carbon (800 mg) at 50° C. After filtering off the catalyst and washing with EtOH, evaporation of the filtrate gave the title compound as a red/brown oil, which started to solidify after several days (quantitative yield). NMR (CDCl3) 1.23 (d, 6H), 2.33 (t, 2H), 3.25 (d, 2H), 3.81 (m, 2 h), 6.65 (d, 2H), 6.79 (d, 2H); m/z 207.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(N(CC)CC)C.[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>CN(C=O)C>[CH2:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:31]([C:21]23[CH2:30][CH:25]4[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]4)[CH2:28]2)[CH2:22]3)=[O:32])[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
(S)-3-Amino-1-benzylpyrrolidine (10 g) and triethylamine (24 ml) were dissolved in DMF (100 ml). Under ice-cooling, 1-adamantanecarbonyl chloride (12.4 g) was added thereto, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. To the obtained residue was added ethyl acetate and the mixture was washed with saturated brine. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=30:1). The obtained eluate was concentrated and IPE was added to the obtained residue. The precipitated crystals were collected by filtration to give (S)-N-(1-benzylpyrrolidin-3-yl)-1-adamantanecarboxamide (14.8 g), melting point 130-132° C.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](OCC)=[O:4].[CH3:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:20])=[O:19])[CH:15]=[CH:14][CH:13]=1>>[CH2:10]([O:11][C:12]1[CH:17]=[C:16]([C:18](=[O:19])[CH2:20][C:3](=[O:4])[CH:2]([F:8])[F:1])[CH:15]=[CH:14][CH:13]=1)[CH3:9]
Reactant: CCOc1cccc(C(C)=O)c1
Reactant: CCOC(=O)C(F)F
Product: CCOc1cccc(C(=O)CC(=O)C(F)F)c1
Yield: 112.1 %

Procedure:
Prepared from commercially available ethyl difluoroacetate (16.0 g, 129 mmol) and 3-ethoxyacetophenone (example C.19 step 1) (14.5 g, 88 mmol) as described in example C.1 step 1 to give the title compound (23.90 g, 112%) as a light red oil. MS (ISN) 241.0 [(M−H)−].
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[C:15]1([C:2]2[NH:3][C:4]3[C:9]([C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(Br)[nH]c2ccccc12
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Yield: 80.6 %

Procedure:
Methyl 2-bromo-1H-indole-3-carboxylate (200 mg, 0.79 mmol), phenylboronic acid (122 mg, 1 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) and cesiumcarbonate (652 mg, 2 mmol) in dioxane/water (20 mL/5 mL) were stirred at room temperature 15 hours. Filterated the solid and the solvent was concentrated in vacuum. The resulted residue was purified by silica gel column (ethyl acetate:petroleum ether=1:2) to obtain methyl 2-phenyl-1H-indole-3-carboxylate as a pale yellow solid (160 mg, 80%) LRMS (M+H+) m/z: calcd 251.1 found 251.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([CH3:31])([N:12]2[C:28]3[C:15](=[CH:16][C:17]4[O:18][CH2:19][C:20]5[N:25]([C:26]=4[CH:27]=3)[C@H:24]([CH3:29])[C:23](=[O:30])[NH:22][N:21]=5)[CH:14]=[CH:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:32]>>[ClH:32].[CH3:29][C@@H:24]1[C:23](=[O:30])[NH:22][N:21]=[C:20]2[N:25]1[C:26]1[CH:27]=[C:28]3[N:12]([C:10]4([CH3:31])[CH2:9][NH:8][CH2:11]4)[CH:13]=[CH:14][C:15]3=[CH:16][C:17]=1[O:18][CH2:19]2
Reactant: C[C@@H]1C(=O)NN=C2COc3cc4ccn(C5(C)CN(C(=O)OC(C)(C)C)C5)c4cc3N21
Agent: Cl
Product: C[C@@H]1C(=O)NN=C2COc3cc4ccn(C5(C)CNC5)c4cc3N21
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of HCl (4M in EtOAc, 40 mL) was added 3-methyl-3-((R)-1-methyl-2-oxo-1,2,3,5-tetrahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-azetidine-1-carboxylic acid tert-butyl ester (4 g, 9.4 mmol) at 0° C. and the reaction mixture was stirred for 30 min. The resulting precipitate was collected by filtration and recrystallized in EtOH to give (R)-1-Methyl-10-(3-methyl-azetidin-3-yl)-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one hydrochloride (2.6 g, 85%). 1H NMR (CD3OD, 400 MHz): δ 7.27 (d, J=12.8 Hz, 2H), 6.84 (s, 1H), 6.50 (s, 1H), 5.04 (d, J=6.5 Hz, 1H), 4.79 (m, 2H), 4.62-4.55 (m, 4H), 1.89 (s, 3H), 1.47 (d, J=6.5 Hz, 3H). LC/MS (Table 1, Method 5) Rt=1.988 min; MS m/z: 326 [M+1]+. SFC (Table 1, Method 37) Rt=2.169 min.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][C:16]1[CH:17]=[C:18]2[CH2:41][C:23]3([C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:24]3=[O:40])[O:22][C:19]2=[N:20][CH:21]=1>CC(C)=O>[O:40]=[C:24]1[N:25]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:38])[CH3:39])[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:31]2[C:23]21[O:22][C:19]1=[N:20][CH:21]=[C:16]([C:15]([OH:3])=[O:14])[CH:17]=[C:18]1[CH2:41]2
Reactant: CC(C)=O
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(CO)cnc3O2)c2cccnc21
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(C(=O)O)cnc3O2)c2cccnc21

Procedure:
Freshly prepared Jones reagent was added drop wise to a solution of 5-(hydroxymethyl)-1′-((2-(trimethylsilyl)ethoxy)methyl)-3H-spiro[furo[2,3-b]pyridine-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.24 g, 0.60 mmol) in acetone (10 mL) at 0° C. until the starting material was completely consumed. The acidic mixture was neutralized carefully with saturated aqueous sodium bicarbonate solution and acidified with saturated aqueous citric acid solution to pH 5-6, then extracted with ethyl acetate (5×). The combined organic layers were dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane to give the title compound as a racemic mixture. MS: m/z=414.2 (M+1); 1H NMR (300 MHz, CD3OD): δ 8.70 (d, 1H, J=1.8 Hz), 8.34 (dd, 1H, J=1.5, 5.3 Hz), 8.29 (d, 1H, J=1.8 Hz), 7.89 (dd, 1H, J=1.5, 7.4 Hz), 7.19 (dd, 1H, J=5.3, 7.4 Hz), 5.26 (s, 2H), 3.78-3.65 (m, 4H), 0.95 (t, 2H, J=8 Hz), 0.005 (s, 9H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:12]=3[S:11]2)=[CH:6][CH:5]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(O)(=O)C>[ClH:28].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:29](=[O:31])[CH3:30])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:12]=3[S:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 1 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 2 ml of acetic anhydride and 2 ml of acetic acid is stirred at 110° C. for 4 hours. Then, the reaction mixture is evaporated under reduced pressure to remove solvent. Ether is added to the residue, and the precipitated crystals are collected by filtration. 1.08 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained. Recrystallization of the product from a mixture of chloroform, ethanol and ether gives crystals (needles) melting at 159°-161° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)=[O:4].[NH3:27]>CO.ClCCl>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[CH2:17][C:16]1[C:7]2[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=2[NH:5][C:3](=[O:4])[CH2:2][N:27]=1
Reactant: COc1cc(NC(=O)CBr)c(C(=O)Cc2ccc(Cl)c(Cl)c2)cc1OC
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(Cc1ccc(Cl)c(Cl)c1)=NCC(=O)N2
Temperature: 40 °C
Yield: 35 %

Procedure:
2-Bromo-N-{2-[2-(3,4-dichloro-phenyl)-acetyl]-4,5-dimethoxy-phenyl}-acetamide (5.25 g, 11.39 mmol) was placed at −10° C. under nitrogen. Ammonia in methanol (7N, 55 ml) was added dropwise at −10° C. and the reaction mixture was heated at 40° C. for 2.5 h, and then at reflux (75° C.) for 1 h. The solvent was evaporated under vacuum yielding a yellow solid which was dissolved in dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. Flashchromatography (dichloromethane/methanol, 18/1) yielded the expected product as a yellow solid (1.5 g, 35%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:45][CH:46]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:47][S:48][CH2:49][CH:50]([CH3:54])[C:51](O)=[O:52])(=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].O>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:51](=[O:52])[CH:50]([CH3:54])[CH2:49][S:48][CH2:47][CH:46]([O:45][C:28](=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[CH:12][CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCC(C)C(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCC(C)C(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 4-aminobenzoylglutamic acid di-t-butyl ester (378 mg) in pyridine (5 ml), phosphorus trichloride (0.044 ml) was added, followed by stirring at room temperature for 2 hours. To this solution, 6,7-bis(palmitoyloxy)-2-methyl-4-thiaheptanoic acid as obtained in Reference Example 42 (336 mg) was added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate =2:1) to yield the title compound (315 mg, yield 62%) as a wax-like substance.