Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:31])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C2CCC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C2CCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-cyclobutylpiperazin-1-yl)quinolin-7-yl]ethanone (0.0692 g, 0.201 mmol) and ammonium acetate (0.155 g, 2.01 mmol) in methanol (0.8 mL) and acetonitrile (0.8 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.50 mL, 0.50 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H26ClN4 (M+H)+: m/z=345.2; Found: 345.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][CH2:18][OH:19])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][CH:18]=[O:19])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CCO)cc(OC)c1OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cc(CC=O)cc(OC)c1OCc1ccccc1
Reaction time: 6 h
Yield: 57.9 %

Procedure:
To a solution of 2-(4-benzyloxy-3,5-dimethoxy-phenyl)-ethanol (1.0 g, 3.3 mmol) in dichloromethane (25 mL) was added Dess-Martin reagent (1.54 g, 3.6 mmol) and water (59 μL). After completion of addition the reaction continued to stir for 6 hours. The resulting precipitate was filtered off and the filtrate was concentrated. The crude material was purified using silica gel chromatography (gradient from 1:2 ethyl acetate:hexane to 1:1 ethyl acetate:hexane) to obtain the desired compound as a yellow oil (547 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C=O)C>[CH3:19][N:20]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:16](=[O:18])/[CH:15]=[CH:14]/[C:10]2[CH:11]=[N:12][CH:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:9]=2)=[CH:33][CH:34]=1)[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(-c2cncc(/C=C/C(=O)O)c2)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cncc(/C=C/C(=O)Nc3ccc(CN(C)C4CCOCC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
To a solution of (E)-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic acid (150 mg), 4-[N-methyl-N-(tetrahydro-pyran-4-yl)aminomethyl]aniline (168 mg) and triethylamine (0.10 ml) in DMF (10 ml) was added diethyl cyanophosphate (0.12 ml) at 0° C., and the mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. To the residue was added water, the mixture was extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:2) to give (E)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]-phenyl]-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic amide (Compound 215) (24 mg) as yellow solid.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH2:19])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[F:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:32]([C:27]2[C:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:33])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Reactant: O=C(O)c1ncccc1-c1ncccn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ncccc1-c1ncccn1

Procedure:
A solution of (1S,2S)-1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 34; 379 mg, 1.44 mmol), 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 290 mg, 1.44 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (34 mg, 0.250 mmol) (294 mg, 2.16 mmol), EDC (415 mg, 2.16 mmol) and triethylamine (0.604 ml, 4.32 mmol) in DCM (1 ml) was stirred at room temperature for 16 hours. The reaction was added partitioned between DCM and as saturated solution of sodium bicarbonate. The organics were filtered through a hydrophobic frit and loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (C18 silica, 0-100% water (0.1% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].N([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=C=O>O1CCOCC1>[O:10]=[C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[O:1]1.[CH3:20][CH2:19][CH:18]([C:2]([NH2:3])=[O:1])[CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCN=C=O
Agent: O=c1[nH]c2ncccc2o1
Solvent: C1COCCO1
Product: CCCCC(CC)C(N)=O

Procedure:
200 mg (1.47 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted in analogy to Example 1 with 207 mg (1.47 mmol) of 1-isocyanatoheptane in dioxane at 80° C. Yield: 416 mg (10%), M+H+: 278.15.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:34]=[N:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.989 min, m/z=403.1; 1H NMR (CDCl3) 1.10 (s, 3H), 1.17 (s, 3H), 1.52 (d, 3H), 2.13-2.28 (m, 6H), 2.47 (m, 1H), 2.87 (m, 1H), 3.95 (s, 3H), 5.70 (m, 1H), 6.79 (d, 1H), 7.02 (d, 2H), 7.21-7.38 (m, 6H), 7.58 (d, 1H), 8.27 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].Br[C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[F:13][CH:12]([F:14])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:26]3[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=3)=[C:7]2[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (180 mg, 72%). MS (ISN) 497.0 [(M−H)−]; mp 225° C.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:42]2[N:43]=[C:44]([NH:47]C(OC(C)(C)C)=O)[S:45][CH:46]=2)\[C:23]([NH:25][C@H:26]2[C@@H:29]([CH2:30][N:31]3[CH2:35][CH2:34][NH:33][C:32]3=[O:36])[N:28]([S:37]([OH:40])(=[O:39])=[O:38])[C:27]2=[O:41])=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(OC(C1(O/N=C(/C2N=C(NC(OC(C)(C)C)=O)SC=2)\C(N[C@H]2[C@@H](CN3CCNC(=O)N3)N(S(O)(=O)=O)C2=O)=O)CC1)=O)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][C:44]1[S:45][CH:46]=[C:42](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]2)/[C:23](=[O:24])[NH:25][C@H:26]2[C@@H:29]([CH2:30][N:31]3[CH2:35][CH2:34][NH:33][C:32]3=[O:36])[N:28]([S:37]([OH:40])(=[O:39])=[O:38])[C:27]2=[O:41])[N:43]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCNC2=O)cs1
Agent: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCNC(=O)N2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCNC2=O)cs1
Yield: 10 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxoimidazolidin-1-yl)methyl)azetidine-1-sulfonic acid, (3S,4R)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((3-oxo-1,2,4-triazinan-1-yl)methyl)azetidine-1-sulfonic acid (48 mg, 61 μmol), DCM (0.61 mL), and TFA (0.28 mL, 3.7 mmol) for 4 h. The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; AcN-water with 0.1% formic acid modifier, 60 mL/min) affording the title compound (3.6 mg, 10%). LCMS: Rt=0.45 min, m/z=518.1 (M+1), Method 2m_acidic; 1H NMR (500 MHz, D2O): δ 7.01 (s, 1H), 5.32 (d, J=5.5 Hz, 1H), 4.53-4.39 (m, 1H), 3.61 (dd, J=14.8, 6.9 Hz, 1H), 3.56-3.41 (m, 2H), 3.35-3.21 (m, 3H), 1.46-1.19 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].[C:14](N1C=CN=C1)([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:15]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)n2ccnc2)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 92.8 %

Procedure:
To a mixture of 4-amino-2-methoxy-benzoic acid methyl ester (1.000 g, 5.246 mmol, Maybridge) in N,N-dimethyl formamide (20.0 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 919.8 mg, 5.502 mmol). After it was stirred at rt for 21 hrs under an argon atmosphere, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-[(imidazole-1-carbonyl)-amino]-2-methoxy-benzoic acid methyl ester (1.34 g, 4.87 mmol, 92.8%) which was used without further purification.
Reaction SMILES: [C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:19]([CH3:26])[CH2:20][C:21]([O:23]CC)=[O:22])[CH:17]=2)[N:12]([C:27](=[O:48])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[C:31]([O:46][CH3:47])[CH:30]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:19]([CH3:26])[CH2:20][C:21]([OH:23])=[O:22])[CH:17]=2)[N:12]([C:27](=[O:48])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[C:31]([O:46][CH3:47])[CH:30]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)c1ccccc1)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CC(=O)N2CCN(C(=O)c3ccccc3)c3cc(C(C)CC(=O)O)ccc32)ccc1NC(=O)Nc1ccccc1C
Temperature: 40 °C
Yield: 12.6 %

Procedure:
A stirred solution of ethyl 3-(4-benzoyl-1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinoxalin-6-yl)-butanoate [0.124 g, Reference Example 16(a)] in methanol (5 ml) was treated with sodium hydroxide solution (764 μl, 15%). The resulting mixture was heated to reflux for 30 minutes, then cooled to 40° C. and then evaporated (40 mbar, 40° C.). The residue was treated with distilled water (40 ml) and the aqueous solution was washed three times with ether (20 ml), then treated with hydrochloric acid (4 ml, 1M) and then extracted three times ethyl acetate (25 ml). The combined extracts were dried over magnesium sulfate then evaporated to dryness (40 mbar, 40° C.). The crude residue (91 mg) was subjected to preparative thin layer chromatography on silica(20×20 cm plates, 0.25 mm thickness) eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give the title compound as a white powder (15 mg). 1H NMR (400 MHz, (CD3)2SO, at a temperature of 373° K.]: δ0.92 (d, J=7 Hz, 3H); 2.16 (d, J=7.5 Hz, 2H); 2.27(s, 3H); 2.80 to 3.05 (m, 1H); 3.84 (s, 3H); 3.94 (m, 2H); 3.96 (s, 2H); 4.01 (m, 2H); 6.60 (broad s, 1H); 6.76 (broad d, J=8 Hz, 1H); 6.88 (broad s, 1H); 6.95 to 7.05 (m, 2H); 7.10 to 7.20 (m, 4H); 7.33 (broad t, J=7.5 Hz, 2H); 7.40 (broad t, J=7.5 Hz, 1H); 7.56 (d, J=8 Hz, 1H); 7.68 (broad d, J=8 Hz, 1H); 8.04 (d, J=8.5 Hz, 1H); 8.23 (broad s, 1H); 8.29 (broad s, 1H). MS (ES): 621 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[O:7][N:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:45][C:46]1[CH:47]=[C:48]([CH:62]=[CH:63][CH:64]=1)[CH2:49][NH:50][C:51]([NH:53][C:54]1[S:55][CH:56]=[C:57]([CH2:59][NH:60][CH3:61])[N:58]=1)=[O:52]>CN(C)C=O.O>[F:45][C:46]1[CH:47]=[C:48]([CH:62]=[CH:63][CH:64]=1)[CH2:49][NH:50][C:51](=[O:52])[NH:53][C:54]1[S:55][CH:56]=[C:57]([CH2:59][N:60]([CH3:61])[C:10]([C:9]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][O:7][C:8]=2[CH3:13])=[O:12])[N:58]=1
Reactant: CNCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reactant: COC(=O)c1noc(C)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1noc(C)c1C(=O)N(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-(methoxycarbonyl)-5-methylisoxazole-4-carboxylic acid (1 mmol) was dissolved in N,N-dimethylformamide (5 ml), then diisopropylethylamine (1.2 eq.) and TBTU (1.2 eq) was added and stirred at room temperature for 5 minutes. 1-(3-fluorobenzyl)-3-(4-((methylamino)methyl)thiazol-2-yl)urea (1.0 mmol) was added and stirred overnight. Water (20 ml) was added to the reaction. The precipitate was filtered, washed with water and dried. The crude was purified by column using 0-100% gradient of 10% MeOH/EtOAc and hexanes to afford methyl 4-(((2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)methyl)(methyl)carbamoyl)-5-methylisoxazole-3-carboxylate.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[O:11][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=2[CH:14]=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=2[CH:14]=1
Reactant: Cc1cc2ccc([N+](=O)[O-])cc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2cc(CBr)oc2c1

Procedure:
N-Bromosuccinimide ("NBS") (1.11 g, 6.2 mmole) was added to a solution of 2-methyl-6-nitrobenzofuran (1.00 g, 5.65 mmole) and azobisisobutyronitrile (20 mg) in carbon tetrachloride and the mixture was heated at reflux temperature for 11/2 hours in the presence of a bright light. The solvent was then evaporated and the residue dissolved in methylene chloride, washed with water, dried (MgSO4), evaporated to dryness and purified by column chromatography on silica eluting with methylene chloride/hexane (7:3). The product-containing fractions were combined and evaporated to give the title compound, yield 1.43 g. 'H-N.m.r. clearly showed that the product contained 20% of 2-dibromomethyl-6-nitrobenzofuran, however, it was not considered necessary to remove this and the product was used directly without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:2]1.C(O)(=[O:18])C.CS(C)=O.Cl>O>[O:18]=[C:2]1[CH:3]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: COC(=O)CCc1c[nH]c2ccccc12
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCC1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
A mixture of methyl 3-indolepropionate (5.00 g, 0.0246 mol), acetic acid (10 mL), dimethylsulfoxide (26 mL, 0.369 mol, 15 eq.) and concentrated hydrogen chloride (37%) (22 mL, 0.738 mol, 30 eq.) was stirred at ambient temperature for 2.5 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (30% ethyl acetate in hexanes) to afford the title compound as an oil (5.28 g, 98%); 1H NMR (DMSO-d6); δ2.03-2.10 (m, 2H); 2.32-2.39 (m, 2H); 3.46 (t, J=6.4 Hz, 1H); 3.54 (s, 3H); 6.81 (d, J=7.6 Hz, 1H); 6.93-6.97 (m, 1H); 7.15-7.17 (m, 1H); 7.24 (d, J=7.6 Hz, 1H);
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[CH2:7]([O:8][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OCc1ccccc1
Product: COc1ccc2c(OCc3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from phenyl-methanol, (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-benzyloxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10](Cl)=[O:11].[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)C1C=CC=CC=1>>[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:10]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:11]
Reactant: O=C(Cl)N1Cc2ccccc2C1
Reactant: O=C(NCCCCO)c1ccccc1
Product: O=C(NCCCCO)N1Cc2ccccc2C1
Yield: 97 %

Procedure:
1,3-Dihydro-isoindole-2-carboxylic acid-(4-hydroxybutyl)amide (27B) is prepared from 27A as described for 1D.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12]([N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]>CCOC(C)=O.CCCCCC>[C:12]([N:15]1[CH2:20][CH2:19][C:18]2([CH2:10][C:9](=[O:11])[C:3]3[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][C:4]=3[O:21]2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC2(CC1)CC(=O)c1c(O)cccc1O2

Procedure:
2',5'-Dihydroxyacetophenone and 1-acetyl-4-piperidone were condensed according to the method of Example 434 to give the ketone as a yellow solid, m.p. 114°-116° C. (from EtOAc/hexane).
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([O:8][C:9](=[O:40])[C:10](=O)[CH2:11][S:12][C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[C:19]1[N:25]([CH3:38])[C:26](=[O:37])[C:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])=[CH:28][C:18]2=1)=[NH:14])[CH3:7].[OH-].[Na+]>O>[CH2:6]([O:8][C:9]([C:10]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19]2[N:25]([CH3:38])[C:26](=[O:37])[C:27]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=4[Cl:36])=[CH:28][C:18]3=2)[S:12][CH:11]=1)=[O:40])[CH3:7]
Reactant: CCOC(=O)C(=O)CSC(=N)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1csc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3 ml of H2SO4 are added to compound A, 3-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indole-6-carboximidoylsulphanyl]-2-oxopropionic acid ethyl ester obtained above and the mixture is stirred at ambient temperature for 16 h. 15 ml of H2O and 5 ml of 1M NaOH are added. The mixture is extracted with EtOAC and concentrated without drying over MgSO4.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[N:26][C:25]=1Cl.C(N(CC)CC)C>C(#N)C>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[N:26][C:25]=1[NH:1][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CN
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)cnc1NCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 36.7 %

Procedure:
To a solution of 2-amino-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.27 g, 0.97 mmol) in acetonitrile (5 mL) was added 2,5-dichloro-nicotinic acid methyl ester (0.20 g, 0.97 mmol) and triethylamine (0.135 mL, 0.97 mmol). The reaction was refluxed for 2 hours. The reaction was concentrated and purified by chromatography on silica gel to give the title compound (0.16 g).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][NH:8][C:9](=[O:27])[CH:10]([O:24][CH2:25][CH3:26])[N:11]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])=[N:12]2)=[CH:5][CH:4]=1)#[N:2].I[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[C:14]([CH3:16])=[CH:15][N:11]([CH:10]([C:9](=[O:27])[NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:29][CH:28]=2)[O:24][CH2:25][CH3:26])[N:12]=1)[CH3:36]
Reactant: CCOC(=O)CI
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)n1cc(C)c(-c2ccccc2O)n1
Product: CCOC(=O)COc1ccccc1-c1nn(C(OCC)C(=O)NCc2ccc(C#N)cc2)cc1C

Procedure:
Using an analogous procedure as described in example 11.2 (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-[3-(2-hydroxy-phenyl)-4-methyl-pyrazol-1-yl]-acetamide was reacted with ethyl iodoacetate to give (RS)-(2-{1-[(4-cyano-benzylcarbamoyl)-ethoxy-methyl]-4-methyl-1H-pyrazol-3-yl}-phenoxy)-acetic acid ethyl ester. White amorphous solid. MS 477.5 ([M+H]+)