Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=[CH:14][C:13]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:10])=[CH:5][CH:4]=1.C(O)(=O)C(O)=O.[NH2:37][CH2:38][P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:29][C:26]([O:25][C:24]([NH:23][C:13]1[CH:14]=[CH:15][C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:17][C:12]=1[NH:11][C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:37][CH2:38][P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:8][CH:7]=1)=[O:10])=[O:30])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Reactant: CCOP(=O)(CN)OCC
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CNCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1)OCC

Procedure:
1,1-dimethylethyl [2-({[4-(bromomethyl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate (500 mg, 1.026 mmol), diethyl (aminomethyl)phosphonate oxalate (791 mg, 3.08 mmol), and DIPEA (1.254 mL, 7.18 mmol) were stirred in DMF (6 mL) at 50° C. overnight. Room temperature was attained, H2O: was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave diethyl [({[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}amino)methyl)phosphonate as a colourless gum. MS: cal'd 574 (MH+), exp 574.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:12]1[CH:25]=[C:24]2[C:15]([O:16][C:17]3[C:18]([F:36])=[CH:19][C:20]([O:34][CH3:35])=[CH:21][C:22]=3[C:23]32[CH:29]([CH2:30][O:31][CH3:32])[S:28][C:27]([NH2:33])=[N:26]3)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].N#N.CC(N)CC1C=CC=CC=1.OP(O)(O)=O>O1CCOCC1.O>[F:36][C:18]1[C:17]2[O:16][C:15]3[C:24](=[CH:25][C:12]([C:7]4[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)[C@@:23]3([C@@H:29]([CH2:30][O:31][CH3:32])[S:28][C:27]([NH2:33])=[N:26]3)[C:22]=2[CH:21]=[C:20]([O:34][CH3:35])[CH:19]=1
Reactant: COCC1SC(N)=NC12c1cc(Br)ccc1Oc1c(F)cc(OC)cc12
Reactant: OB(O)c1cccnc1F
Agent: CC(N)Cc1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC[C@H]1SC(N)=N[C@]12c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OC)cc12
Temperature: 100 °C
Yield: 59.2 %

Procedure:
To a sealed vessel was charge with (2-fluoropyridin-3-yl)boronic acid (1.543 g, 10.95 mmol), 7′-bromo-4′-fluoro-2′-methoxy-5-(methoxymethyl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (1.34 g, 3.04 mmol, prepared as in Method CC25), potassium carbonate (1.5M in water) (6.08 mL, 9.12 mmol) in dioxane (15 mL). It was purged with N2 and finally AmPHOS (0.13 g, 0.18 mmol) was added. The mixture was heated in oil bath at 100° C. for 20 min. The reaction mixture was allowed to cool to rt. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude material as an orange oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a gold Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 30% to 50% to 75% DCM/MeOH/NH4OH in 40% EtOAc in heptane, to provide (4S,5S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-methoxy-5-(methoxymethyl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (817 mg, 1.80 mmol, 59% yield) as light brown foam.
Reaction SMILES: [C:1]([C@@:11]([C:28]([OH:30])=[O:29])([OH:27])[C@@:12]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([OH:16])[C:13]([OH:15])=[O:14])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.O.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>CO>[C:17]([C@@:12]([C:13]([OH:15])=[O:14])([OH:16])[C@@:11]([C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([OH:27])[C:28]([OH:30])=[O:29])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Cl:32][C:33]1[CH:34]=[C:35]([C@:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: CO
Product: OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine (S,S)-di-p-anisoyltartaric acid (14.77 g, 35 mmol), water (200 mL) and methanol (200 mL). Heat to reflux. Add dropwise, a solution of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (18.36 g, 70 mmol) in methanol (135 mL). After 1.5 hours, add water (135 mL) and slowly cool to ambient temperature to give a solid. Filter the solid that forms and rinse with water to give the title compound: mp; 201-202° C. (dec). Analysis by HPLC, as described in Example 5.1.1 indicates an enantiomeric excess of 99.9%, (99.9% ee). [α]2D0=+17.9° (c=1.00, dimethylsulfoxide).
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/[C:4]([OH:6])=O.[CH3:9][O:10][C:11]1[C:21]2[CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH2:18][N:17]([CH3:28])[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.P(OP(O)(O)=O)(O)(O)=O.[OH-].[NH4+].Cl[CH2:41]CCl>>[CH3:9][O:10][C:11]1[C:21]2[CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH2:18][N:17]([CH3:28])[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.[CH3:41][O:6][C:4]1[CH:24]=[CH:23][C:22]2[CH:20]([C:21]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:19][CH2:18][N:17]([CH3:16])[CH2:1][C:2]=2[CH:3]=1
Reactant: ClCCCl
Reactant: O=C(O)/C=C/C(=O)O
Agent: COc1cccc2c1C(c1ccccc1)CCN(C)C2
Agent: O=P(O)(O)OP(=O)(O)O
Agent: [NH4+]
Product: COc1ccc2c(c1)CN(C)CCC2c1ccccc1
Temperature: 100 °C
Yield: 28 %

Procedure:
A mixture of the product from step A (1.0 g, 3.74 mmol) and pyrophosphoric acid (25 g) in 1,2-dichloroethane (5 mL) was heated at 100° C. for 1 hour. The reaction mixture was cooled, mixed with ice and adjusted to pH 9 with ammonium hydroxide. The reaction mixture was extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification via MPLC (30% to 50% ethyl acetate/hexanes) provided 6-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (350 mg, 35%) and 8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (280 mg, 28%): 6-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine: 1H NMR (CDCl3, 300 MHz) δ 7.28-7.21 (m, 2H), 7.19-7.13 (m, 2H), 7.06 (d, J=8.0 Hz, 2H), 6.85 (d, J=8.1 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.12 (t, J=4.9 Hz, 1H), 3.82 (d, J=14.3 Hz, 1H), 3.72 (s, 3H), 3.45 (d, J=13.6 Hz, 1H), 2.92-2.85 (m, 1H), 2.75-2.70 (m, 1H), 2.34-2.29 (m, 2H), 2.27 (s, 3H); ESI MS m/z=268 [M+H]+; 8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine: 1H NMR (CDCl3, 500 MHz) δ 7.34 (t, J=7.5 Hz, 2H), 7.26-7.23 (m, 1H), 7.17 (d, J=7.5 Hz, 2H), 6.74 (d, J=2.7 Hz, 1H), 6.61-6.59 (m, 2H), 4.26 (d, J=8.6 Hz, 1H), 3.91-3.90 (m, 1H), 3.76 (s, 3H), 3.70 (d, J=14.1 Hz, 1H), 3.12-3.09 (m, 1H), 2.98-2.93 (m, 1H), 2.35 (s, 3H), 2.32-2.27 (m, 1H), 2.11-2.10 (m, 1H); ESI MS m/z=268 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([CH2:5][NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=1)=[O:4]>CO.[Pd]>[NH2:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[NH:14][CH3:15])[C:7]([NH:6][CH2:5][C:3](=[O:4])[N:2]([CH3:20])[CH3:1])=[O:19]
Reactant: CNc1ccc(C(=O)NCC(=O)N(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(C(=O)NCC(=O)N(C)C)cc1N
Yield: 98 %

Procedure:
3-Amino-N-dimethylcarbamoylmethyl-4-methylamino-benzamide (700 mg) was prepared by following General Procedure B starting from N-dimethylcarbamoylmethyl-4-methylamino-3-nitro-benzamide (800 mg) and Pd—C (160 mg) in methanol (10 mL).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19](O)=[O:20])=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH:26]1[CH2:29][CH2:28][CH2:27]1>>[N:26]1([C:19]([C:18]([NH:17][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:16])([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])[CH2:29][CH2:28][CH2:27]1
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Reactant: C1CNC1
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)N1CCC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid and azetidine (CAN 503-29-7) as starting materials. MS (EI): m/e=386.0 [M+H]+.
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[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44](=O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[CH2:44]([N:24]1[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[CH:43][C:19]=2[CH:20]=[C:21]([C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=3[O-:41])=[CH:32][CH:33]=2)=[O:26])[CH2:22][CH2:23]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3Cc2ccccc2)cc1
Reaction time: 24 h
Yield: 72.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and benzaldehyde (0.22 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 24 hours. To the reaction solution were added benzaldehyde (0.22 g) and sodium triacetoxyborohydride (0.22 g), and the mixture was further stirred for 24 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 90) (168.0 mg) as yellow crystals.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[O:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:12]([OH:13])=[C:9]([O:10][CH3:11])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:11][O:10][C:9]1[CH:8]=[C:7]([CH:15]=[CH:14][C:12]=1[O:13][CH2:3][C:2]#[CH:1])[CH:6]=[O:5]
Reactant: COc1cc(C=O)ccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccc(C=O)cc1OC
Yield: 96.8 %

Procedure:
Propargyl bromide (293 mL, 80% w/v, 1.97 mol) was added to a suspension of vanillin (250 g, 1.64 mol) and potassium carbonate (681 g, 4.93 mol) in MeCN (2.0 L). The suspension was heated to reflux for 6 h and the solvent was removed under reduced pressure. Water was added and the aqueous phase was extracted with EtOAc, washed with water, brine and dried. The solvent was removed under reduced pressure to give 3-methoxy-4-propargyloxybenzaldehyde (302 g, 97%) as yellow crystalline solid; mp 95° C.; δH (400 MHz, CDCl3) 2.56 (t, J=2.5 Hz, 1H, C≡CH), 3.95 (s, 3H, OCH3), 4.86 (d, J=2.5 Hz, 2H, OCH2); 7.14 (d, J5,6=6.8 Hz, 1H, H5), 7.44 (d, J2,6=1.4 Hz, 1H, H2), 7.47 (dd, J5,6=6.8, J2,6=1.4 Hz, 1H, H6), 9.87 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.0, 56.6, 77.2, 77.4, 109.4, 112.5, 126.3, 130.9, 150.0, 152.1, 190.9; HRMS (ESI) Calculated for C11H10O3 [M+H]+, 191.0703 found 191.0706; νmax 1006, 1130, 1259, 1586, 1677, 2119, 2845, 2932, 3266 cm−1.
Reaction SMILES: [Cl-:1].[NH2:2][C:3]1[CH:8]=[CH:7][N+:6]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([S:20](=[O:30])(=[O:29])[N:21]([CH3:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[CH:16][C:15]=2[NH:31][CH3:32])=O)=[CH:5][CH:4]=1>C(#N)C.S(Cl)(Cl)=O.C(OCC)C>[Cl-:1].[NH2:2][C:3]1[CH:8]=[CH:7][N+:6]([CH2:9][CH2:10][C:11]2[N:31]([CH3:32])[C:15]3[CH:16]=[CH:17][C:18]([S:20](=[O:30])(=[O:29])[N:21]([CH3:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:14]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: CNc1ccc(S(=O)(=O)N(C)c2ccccc2)cc1NC(=O)CC[n+]1ccc(N)cc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(CC[n+]1ccc(N)cc1)n2C
Reaction time: 24 h

Procedure:
To a suspension of 4-amino-1-(3-(5-(N-methyl-N-phenylsulfamoyl)-2-(methylamino)phenylamino)-3-oxopropyl)pyridinium chloride (0.2 g, 0.00042 mol) in acetonitrile (8 ml), thionyl chloride (0.2 ml) was added. After boiling the reaction mixture for 10 min, it was left to stand at room temperature for 24 h and then diluted with diethyl ether (8 ml). The precipitate formed was collected by filtration and crystallized from a 10:1 mixture of acetonitrile with dehydrated ethanol. The yield of 4-amino-1-(2-(1-methyl-5-(N-methyl-N-phenylsulfamoyl)-1H-benzo[d]imidazol-2-yl)ethyl)pyridinium chloride was 0.055 g (26%).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]2=[CH:20][C:3]=1[CH2:4][N:5]([CH3:53])[C:6](=[O:52])[C@H:7]([NH:26][C:27]1[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=1)[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:32][CH:31]=[CH:30]3)[C:8]1[CH:24]=[C:23]([CH3:25])[C:11]([C@@H:12]([CH3:22])[CH2:13][O:14][C:15](=[O:21])[NH:16]2)=[CH:10][CH:9]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CS(C)=O.[C]=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[C:48]([O:47][C:45]([N:37]([C:38]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:44])[C:33]1[C:34]2[C:29](=[CH:28][C:27]([NH:26][C@H:7]3[C:6](=[O:52])[N:5]([CH3:53])[CH2:4][C:3]4[CH:20]=[C:17]([CH:18]=[CH:19][C:2]=4[C:15]([O:14][CH3:13])=[O:21])[NH:16][C:15](=[O:21])[O:14][CH2:13][C@H:12]([CH3:22])[C:11]4[CH:10]=[CH:9][C:8]3=[CH:24][C:23]=4[CH3:25])=[CH:36][CH:35]=2)[CH:30]=[CH:31][N:32]=1)=[O:46])([CH3:50])([CH3:51])[CH3:49]
Reactant: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(Br)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1ccc2cc1CN(C)C(=O)[C@H](Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 166.8 %

Procedure:
To a pressure flask charged with 1B (250 mg, 0.317 mmol), palladium(II) acetate (35.6 mg, 0.158 mmol), TEA (0.132 mL, 0.951 mmol) and dppp (65.4 mg, 0.158 mmol) was dissolved with DMSO (2 mL)/MeOH (1.000 mL). The resulting mixture was charged with carbon monoxide at 25 psi and then stirred at 80° C. under and atmosphere of CO overnight. Reaction mixture was cooled to rt, filtered and concentrated. The resulting residue was dissolved in EtOAc, washed with water. The aqueous layer was then back extracted. The organic layers were combined, washed with brine and dried (Na2SO4). The crude was purified on SQ16 column equilibrated with 1% MeOH in dichloromethane to give 1C (203 mg, 83% yield): MS (ESI) m/z: 768.4 [M+H]+; 1H NMR (400 MHz, MeOD) δ ppm 7.94 (1H, d, J=5.77 Hz), 7.81 (1H, d, J=8.28 Hz), 7.58 (1H, d, J=7.03 Hz), 7.49 (1H, d, J=9.03 Hz), 7.41 (1H, d, J=5.77 Hz), 7.36 (1H, d, J=7.78 Hz), 7.16 (1H, dd, J=9.16, 2.13 Hz), 7.08 (1H, s), 6.78 (1H, d, J=1.76 Hz), 6.64 (1H, dd, J=8.28, 1.76 Hz), 6.14 (1H, s), 5.54-5.66 (2H, m), 4.52 (1H, t, J=10.92 Hz), 3.85 (1H, dd, J=10.54, 4.27 Hz), 3.74 (3H, s), 3.21 (2H, d, J=1.51 Hz), 3.20 (1H, br. s.), 2.18 (3H, s), 1.21 (4H, d, J=7.03 Hz), 1.15 (19H, s).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[S:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(C1N(C[C:34]2[S:35][C:36]([C:39](OC)=O)=[CH:37][CH:38]=2)C(C=O)=CN=1)CCC>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[S:15][CH:14]=2)[C:7](/[CH:10]=[C:16](\[CH2:39][C:36]2[S:35][CH:34]=[CH:38][CH:37]=2)/[C:18]([OH:20])=[O:19])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1csc(C(=O)OC)c1
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)s1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1csc(C(=O)O)c1

Procedure:
The title compound was prepared following the procedures described in Example 1 (v-vi) using 2-n-butyl-1-[(5-carbomethoxy-3-thienyl)methyl]imidazol-5-carboxaldehyde (prepared by the methods described in Example 2 (i-iii)) in place of 2-n-butyl-1-[(5-carbomethoxy-2-thienyl)methyl]-imidazol-5-carboxaldehyde; mp 133°-135° C. (d).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:15])[NH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>C(O)CO.O>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:3][NH:4][C:5]2=[O:15])=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Br)c[nH]c(=O)c2cc1F
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: OCCO
Product: COc1cc2c(N3CCOCC3)c[nH]c(=O)c2cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-7-fluoro-6-methoxyisoquinolin-1(2H)-one (0.5 g, 1.838 mmol) and morpholine (0.4 g, 4.59 mmol) in ethylene glycol (2.5 ml) was added DIPEA (1.031 ml, 5.90 mmol). The reaction was irradiated in microwave at 145° C. for 1.5 h. The reaction was cooled to ambient temperature and diluted with water. The aqueous layer was extracted with EtOAc. The organic layer was washed with 1N HCl, followed by washing with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get the crude compound. The crude compound (0.25 g, 31.8%) was taken to the next step without further purification. MS: MS m/z 279.22 (M++1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:7]=[C:6]([CH3:21])[C:5]=1[S:22]C#N.O.Cl>C(O)C.C(COC)OC>[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:7]=[C:6]([CH3:21])[C:5]=1[SH:22]
Reactant: Cc1ccccc1CC(=O)Nc1cc(C)c(SC#N)c(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Cc1ccccc1CC(=O)Nc1cc(C)c(S)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (2.5 g, 66 mM) was added in portions to an ice-water cooled suspension of 2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]phenyl thiocyanate (B) (5.0 g, 16 mM) in ethanol (100 mL) and dimethoxyethane (100 mL). After 2 hours, water (200 mL) was added to the clear yellow solution. The mixture was acidified to pH4 with 2M HCl and extracted with ethyl acetate. The combined extracts were washed with water, then with saturated sodium chloride solution, and dried (MgSO4). The solvent was removed by evaporation to yield 2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]benzenethiol as a cream coloured solid (4.89 g) which was used without characterisation.
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].[C:17]([O-:20])(=[S:19])[CH3:18].[K+]>C(O)C>[C:17]([S:19][CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15])(=[O:20])[CH3:18]
Reactant: CC([O-])=S
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1CBr
Agent: [K+]
Solvent: CCO
Product: CC(=O)SCc1c([N+](=O)[O-])cc(CO)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 90.2 %

Procedure:
4-bromomethyl-3,5-dinitro benzyl alcohol(800 mg, 2.75 mmol), anhydrous ethanol(10 ml) and potassium thioacetate(380 mg, 3.3 mmol) were charged into a 200 ml 2-neck round bottom flask equipped with condenser, dropping funnel and stirrer and put in an oil bath maintaining 150° C. and having thermocouple. The resulting mixture solution was heated at 100° C. for 30 minutes and cooled to ambient temperature. White solid formed during the reaction was filtered away and the filterate was concentrated by removing the solvent under reduced temperature. Pale yellow solid of 4-acetylsulfanylmethyl-3,5-dinitrobenzyl alcohol (710 mg, 2.48 mmol, yield 90%) was obtained by purification on a silica gel chromatography using 20% ethylacetate-hexane solvent system. Nuclear magnetic resonance (NMR) spectrum showed that the product has identical structure with compound V and the NMR data was set forth below.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[CH2:7].ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl.O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]1[O:25][CH2:7]1
Reactant: C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1cc(C2CO2)cc(C(F)(F)F)c1

Procedure:
A solution of 3,5-bis(trifluoromethyl)styrene (13.3 g) and m-chloroperbenzoic acid (21 g) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. The resulting suspension was diluted with water (100 ml) and dichloromethane (100 ml), and the organic phase was washed further with water (2×100 ml) and saturated brine (100 ml). After drying (MgSO4) the solvent was removed in vacuo and the residue purified by chromatography on silica (eluting with isohexane followed by 10% ethyl acetate in isohexane) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 2.79 (1H, dd J 6.0 Hz and 2.7 Hz), 3.23 (1H, dd J 5.9 Hz and 4.5 Hz), 3.99 (1H, dd J 4,4 Hz and 2.7 Hz), 7,74 (2H,s), 7.82 (1H, s).