Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][N:22]=[CH:21]1>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[N:20]([CH3:19])[CH:21]=[N:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cncc1-c1cc2nc(Cl)ccc2n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 7 h

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 1-methyl-5-(tributylstannyl)-1H-imidazole (0.12 g, 0.31 mmol, Aldrich) in toluene (6.0 mL) was degassed by a stream of nitrogen through the solution. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added and the mixture was stirred at 110° C. for 7 hours. Toluene was removed in vacuo, and the residue was dissolved in MeCN and filtered. Flash chromatography, eluting with a gradient from 0-70% EtOAc in hexanes afforded product as a white solid (35 mg, 35%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[C:18]([O:20][CH2:21][CH3:22])=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:11]4[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[C:18]([O:20][CH2:21][CH3:22])=[CH:19][C:10]=4[N:9]=3)[CH:3]=2)[CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c1)=N2

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-7-ethoxy-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.3) (200 mg, 0.50 mmol) and commercially available 3-tert-butylsulfamoyl-benzeneboronic acid [CAS-no. 221290-14-8] (144 mg, 0.55 mmol) according to the general procedure II. Obtained as an off-white solid (169 mg, 65%). MS (ISP) 559.7 [(M+H)+]; mp 215-218° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]([OH:13])[CH2:9][C:10]([OH:12])=[O:11].C(O)(C(F)(F)F)=O.C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1>CN(C=O)C>[OH:13][CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCCCCC[C@@H](O)CC(=O)O
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCCCCC(O)CC(=O)O

Procedure:
Linear peptide (18) was completed by acylating the peptide resin with the Pfp-ester of D-3-hydroxydecanoic acid in DMF. Again, the use of Pfp ester activation allowed the acid to be coupled with its hydroxyl unprotected. 3-Hydroxydecanoic acid (mp 55°-56° C., 57° C.)21 was synthesized from n-octyl aldehyde by reaction with lithium tert-butyl acetate22 followed by TFA hydrolysis and resolution as the (-)-cinchonidine salt (mp 119°-120° C., 119°-120° C.) which upon neutralization gave (-)-D-3-hydroxydecanoic acid ([a]D =-21.4° C. (c 1.0, CHCl3); lit. [a]D=-17.5°).19The final peptide was cleaved from the resin with TFA (50% in CH2Cl2, 30 min) and lyophilized from dioxane to yield the crude peptide (18). This was readily purified by reverse phase HPLC using a C18 column and an H2O-acetonitrile gradient system containing 0.1% TFA, with the resulting peptide being relyophilized from dilute anhydrous dioxane --HCl to yield (18).HCl as a white solid in 25% overall yield based on resin substitution.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[N:12]([CH2:17][C:18]#[CH:19])[C:11]3=[O:20])=[CH:6][CH:5]=1)([O-])=O.[Sn]>O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[N:12]([CH2:17][C:18]#[CH:19])[C:11]3=[O:20])=[CH:8][CH:9]=1
Reactant: C#CCN1C(=O)C2CC2(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Sn]
Solvent: O
Product: C#CCN1C(=O)C2CC2(c2ccc(N)cc2)C1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 0.54 g of 1-(4-nitrophenyl)-3-propargyl-3-azabicyclo[3.1.0]hexane-2,4-dione and 1.5 g of tin powder in 4 ml of water and 4 ml of water is stirred for 1 hour at 100° C. The reaction mixture is cooled to room temperature and then diluted with 20 ml of water, filtered, and made alkaline with sodium hydroxide solution. The reaction mixture is extracted with ethyl acetate and the organic phase is washed with a dilute aqueous solution of sodium chloride until neutral, dried over magnesium sulfate and concentrated. The residue is recrystallised from ethyl acetate/petroleum ether, affording the title compound with m.p. 106°-109° C. and with Rf=0.12 on thin-layer silica gel plates in the system hexane/ethyl acetate (1:1).
Reaction SMILES: C(N(CC)CCN(CC)CC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:23]([O:26][CH3:27])(=[O:25])[CH3:24].[C:28]([O:32][C:33]([N:35]1[CH2:41][C@H:40]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:39][C@H:36]1[CH:37]=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].[Cl-].[NH4+]>O1CCCC1>[C:28]([O:32][C:33]([N:35]1[CH2:41][C@H:40]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:39][C@H:36]1[CH:37]([OH:38])[CH2:24][C:23]([O:26][CH3:27])=[O:25])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: COC(C)=O
Agent: CCN(CC)CCN(CC)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)CC(O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a mixture of tetrahydrofuran (45 ml) and tetraethylethylenediamine (1.5 ml) were successively added a 1.0M sodium hexamethyldisilazide--tetrahydrofuran solution (0.892 ml) and methyl acetate (71.2 μl) at -78° C. The mixture was stirred for 30 minutes, and then a tetrahydrofuran solution of (2S,4R)-N-tert-butoxycarbonyl-4-(tert-butyldimethylsiloxy)prolinal (196 mg) was added thereto. This solution was stirred for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (heptane-ethyl acetate=3:1) to obtain the title compound [209 mg, yield: 87.1%; (R)-isomer (polar compound):(S)-isomer (less polar compound)=1.82:1].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:19]([CH2:20]I)[CH2:18][C:17]3[C:22]4[C:9]2=[N:10][CH:11]=[N:12][C:13]=4[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:23][CH3:24])=[C:4]([F:27])[CH:3]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]([CH3:20])=[CH:18][C:17]3[C:22]4[C:9]2=[N:10][CH:11]=[N:12][C:13]=4[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:23][CH3:24])=[C:4]([F:27])[CH:3]=1
Reactant: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(Br)cc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)C=C(C)N3c1ccc(Br)cc1F
Temperature: 120 °C

Procedure:
To a solution of 4-(4-bromo-2-fluoro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene (33 mg, 0.06 mmol) (from Example 19, Step F, supra) in toluene (7 mL) was added DBU (0.09 mL, 0.6 mmol) (Fluka). The reaction mixture was heated at 120° C. for 1 hour. The mixture was then diluted with chloroform (100 mL), and washed with H2O. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2 /Et3N (1:1:0.05) as eluent to give the desired 4-(4-bromo-2-fluoro-phenyl)-7,8-dimethoxy-5-methyl-4H-1,3,4-triaza-phenalene as a white solid. (Yield 0.027 g 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([NH2:11])=[N:9][N:10]=[C:4]2[CH:3]=1.[CH:12]1([NH:15][C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[NH2:11][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=3[CH3:23])[C:16]([NH:15][CH:12]3[CH2:13][CH2:14]3)=[O:33])=[CH:3][C:4]2=[N:10][N:9]=1
Reactant: Nc1nnc2cc(Br)ccn12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccn2c(N)nnc2c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A mixture of 7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-amine (0.202 g, 0.95 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.358 g, 1.2 mmol), sodium carbonate (0.439 g, 4.1 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.057 g, 0.081 mmol) in 7 μL of DME/3 mL of H2O/2 mL of EtOH was heated at 80° C. After 2.5 h, the reaction mixture was cooled to 25° C., evaporated onto silica gel and purified by flash column chromatography eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give the title compound as a tan amorphous solid. MS m/z: 308.1 [M+1].
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[N:22][CH:23]=2)[C:13](=[O:30])[C@@H:12]1[CH2:31][O:32][CH3:33])=O)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:29][N:27]([CH2:26][CH2:25][NH:24][C:21]1[N:22]=[CH:23][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][C@@H:12]([CH2:31][O:32][CH3:33])[C:13]2=[O:30])=[CH:19][N:20]=1)[CH3:28]
Reactant: COC[C@H]1C(=O)N(Cc2cnc(NCCN(C)C)nc2)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC[C@@H]1NCCN(Cc2cnc(NCCN(C)C)nc2)C1=O
Yield: 31 %

Procedure:
4-Benzyloxycarbonyl-1-[(2-{[N,N-dimethylaminoethyl]-amino }-pyrimidin-5-yl)-methyl]-3-(S)-methoxymethyl-piperazine-2-one (0.01 g, 0.02 mmol) and 10% Pd on carbon (0.01 g) are stirred in acetic acid (3 mL) under a hydrogen atmosphere for 18 h. The mixture is filtered through Celite@ and is evaporated to provide the intermediate title compound as a clear colorless oil (0.002 g). MS (ES), 323 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Yield: 101.6 %

Procedure:
150 mg of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (described later, produced in Intermediate Production Example 1) was dissolved in 1.0 ml of N,N-dimethylformamide, and to this was added 51 mg of anhydrous potassium carbonate, and 50 mg of methyl bromoacetate was added with stirring at room temperature, then, the mixtures was stirred for 2 hours at 60° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 167 mg of methyl [4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [Compound 1-11 of the present invention].
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1
Reaction time: 1 h

Procedure:
To a solution of cis-3-hydroxycyclobutane carboxylic benzyl ester (see WO03000657A1)(18.0 g, 87.5 mmol) in dichloromethane (155 m/L) was added triethylamine (18.3 mL, 131 mmol), and then thereto was added dropwise a solution of methanesulfonyl chloride (8.16 mL, 105 mmol) in dichloromethane (20 mL) at 0° C. for 15 minutes. The mixture was stirred for 1 hour, and then the reaction solution was washed with aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the titled compound (24.9 g, quant.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[CH:17]=[C:16](Cl)[N:15]=[C:14]([O:19][CH3:20])[N:13]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[N:13]=[C:14]([O:19][CH3:20])[N:15]=[C:16]([C:29]4[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=4)[CH:17]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COc1nc(Cl)cc(NCc2ccc3occc3c2)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
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: COCCOC
Product: COc1nc(NCc2ccc3occc3c2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 34.2 %

Procedure:
Argon is bubbled through a mixture of benzofuran-5-ylmethyl-(6-chloro-2-methyoxy-pyrimidin-4-yl)-amine (100 mg, 0.35 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [131 mg, 0.63 mmol, see Example 49(b) step 2]. Cs2CO3 (342 mg, 1.05 mmol), and tetrakis(triphenylphosphine)palladium (0) (46 mg, 0.04 mmol) in ethylene glycol dimethyl ether (1.7 mL) and water (0.3 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 6 hours the heating is turned off and the mixture is allowed to cool to ambient temperature upon standing for 24 hours. The mixture is diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{6-[(benzofuran-5-ylmethyl)-amino]-2-methyoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [50 mg, 34%. Example 93] as a solid. LCMS RT=2.05 minutes, MS: 418 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]1>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(C)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)ccc1OCCN1CCC(C)CC1

Procedure:
Prepared analogously to Example 3.1.b. from 1-[2-(2-methoxy-4-nitrophenoxy)ethyl]-4-methylpiperidine. Yield: 0.51 g (81.1% of theory); C15H24N2O2 (M=264.37); calc.: molecular ion peak (M+H)+: 265; found: molecular ion peak (M+H)+: 265; Rf value: 0.3 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:31][C:32]([O:34]CC)=[O:33])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[NH:24])=[CH:21][CH:20]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[ClH:1].[C:2]1([N:8]([CH2:31][C:32]([OH:34])=[O:33])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[NH:24])=[CH:21][CH:20]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(Cc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 13 from 4-[(5-(N-phenyl-N-ethoxycarbonylmethyl-aminocarbonyl)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:18][C:19]([C:21]1[N:22]=[CH:23][C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:9][C:19]([C:21]1[N:22]=[CH:23][C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:25]=2)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(CN)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)c1ccccc1
Temperature: 150 °C
Yield: 76.2 %

Procedure:
A mixture of 3-amino-2-phenyl-propionic acid tert-butyl ester (90 mg), 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (40 mg) and DBU (0.030 mL) in DMA (1 mL) was heated in an oil bath (150° C.) for 1.5 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (50 mg). LC-MS ESI+: 485 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[N:11][N:12]=2)[CH:9]=1)(=[O:3])[CH3:2].Br.C(O)(=O)C.[Br:18]N1C(=O)CCC1=O.ClCCl>C(O)(=O)C.C(OCC)(=O)C>[Br:18][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[N:11][N:12]=2)[CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc2nnnn2c1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc2nnnn2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Acetyl tetrazolo[1,5-a] pyridine (10 g, 62 mmol) in acetic acid (160 mL) was treated with 30% HBr/acetic acid (14.7 mL, 247 mmol) at 0° C. N-bromosuccinimide (11 g, 62 mmol) was slowly added and the reaction stirred for 30 minutes. Another 4 equivalents of 30% HBr/acetic acid (14.7 mL, 247 mmol) was slowly added and the reaction was allowed to warm to room temperature. After 3 hours, the reaction was diluted with ethyl acetate (500 mL) and washed with water (3×300 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford an oil. Hexanes (75 mL) and dichloromethane (10 mL) were added to the oil and reconcentrated to afford a yellow solid (12.8 9, 86%). Rf =0.2 (CH2Cl2); mp 108-110° C.; 1H NMR (300 MHz, CDCl3) δ 10.2 (s, 1 H), 8.29 (dd, J=9, 10 Hz, 1 H), 8.18 (dd, J=8, 10 Hz, 1 H), 5.06 (s, 2 H); MS (EI) m/z 241 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:14]([NH:15][CH3:16])=[CH:13][C:5]([CH:6](O)CS(C)(=O)=O)=[CH:4][C:3]=1[NH:17][CH3:18].C[O-].[Na+].[NH:22]([CH2:29][CH2:30][C:31]#[N:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CS(C)=O>[NH:22]([CH:29]=[C:30]([CH2:6][C:5]1[CH:13]=[C:14]([NH:15][CH3:16])[C:2]([Cl:1])=[C:3]([NH:17][CH3:18])[CH:4]=1)[C:31]#[N:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNc1cc(C(O)CS(C)(=O)=O)cc(NC)c1Cl
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1cc(CC(C#N)=CNc2ccccc2)cc(NC)c1Cl

Procedure:
A mixture of 13.2 g. of 4-chloro-3,5-bis(methylamino)-α-[(methylsulfonyl)-methyl]benzyl alcohol, 3.6 g. of sodium methylate and 9.6 g. of β-anilinopropionitrile in 80 ml. of dimethylsulfoxide was stirred for 5 hours under nitrogen at 50° C. The mixture was poured into 200 ml. of ice water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained α-(anilinomethylene)-4-chloro-3,5-bis(methylamino)hydrocinnamonitrile having a melting point of 142°-147° C.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[CH:10][CH:9]=1)(=[O:5])=[O:4])[CH3:2].[C:24]1([CH3:42])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=[C:32]([C:38]([F:41])([F:40])[F:39])[N:31]=2)[CH:25]=1>C(#N)C.CN(C)C1C=CN=CC=1>[C:24]1([CH3:42])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH2:36][NH:37][C:15](=[O:23])[NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:13][CH:12]=3)=[CH:34][CH:33]=[C:32]([C:38]([F:40])([F:39])[F:41])[N:31]=2)[CH:25]=1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: CCS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCS(=O)(=O)NCc1ccc(NC(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)cc1
Temperature: 50 °C
Yield: 44.9 %

Procedure:
To a solution of phenyl 4-(ethylsulfonamidomethyl)phenylcarbamate (74 mg, 0.22 mmol) in acetonitrile (3 mL) was added 4-dimethylaminopyridine (27 mg, 0.22 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (59 mg, 0.22 mmol) at room temperature. The reaction mixture was heated to 50° C. for 15 h. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethylacetate. The organic part was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give N-(4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)ethanesulfonamide (example 82) (50 mg, 45%).