Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[N:6][CH:7]=1.[CH2:19](C([Sn])=C(CCCC)CCCC)[CH2:20]CC.C(OCC)(=O)C>CN(C=O)C>[CH:19]([C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[N:6][CH:7]=1)=[CH2:20]
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(Br)cnn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 90.8 %

Procedure:
5-Bromo-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (2.0 g, 0.0066 mole), tributylvinyltin (2.3 g, 0.00726 mole) and Pd(PhCH2)Cl(Ph3P)2 (0.1 g, 0.000132 mole) were heated at 100° C. in DMF (75 mL) for 1 hour. The mixture was then poured into ethyl acetate and extracted 2×200 mL with aqueous KF, brine, dried (MgSO4), filtered through a pad of silica gel with ethyl acetate and evaporated in vacuo. The crude oil was purified by silica gel chromatography to give 5-ethenyl-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (1.62 g, 91% yield) as an off-white solid.
Reaction SMILES: [N:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]=[C:3]([C:9](N(OC)C)=[O:10])[CH2:2]2.[CH3:15][Li].[Br-].[Li+].P(=O)(O)(O)O>O1CCCC1.C(OCC)C>[C:9]([C:3]1[CH2:2][N:1]2[CH2:8][CH:5]([CH:4]=1)[CH2:6][CH2:7]2)(=[O:10])[CH3:15]
Reactant: CON(C)C(=O)C1=CC2CCN(C1)C2
Reactant: [Li]C
Agent: O=P(O)(O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)C1=CC2CCN(C1)C2
Temperature: -70 °C

Procedure:
A solution of (±)1-azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxy-N-methylcarboxamide (D8) (0.40 g, 2.0 mmole) in dry tetrahydrofuran (20 ml) was cooled to -70° C., under a nitrogen atmosphere, and treated dropwise over 15 minutes with methyllithium (1.47 ml of a 1.5 m solution in diethyl ether as the complex with lithium bromide, 2.2 mmole). The temperature was maintained at -70° C. for 30 minutes, and then allowed to warm to 0° C. over 1.75h. The reaction was cooled to -20° C. and poured into a 1M solution of orthophosphoric acid (20 ml) cooled below 0° C. The organic layer was separated, and the aqueous phase was saturated with potassium carbonate, and extracted exhaustively with chloroform. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give a pale yellow oil (0.33 g) which was distilled in a kugelrohr at 150° C./0.1 mmHg to give the title compound (D10) as a colourless liquid (0.28 g, 93%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:9]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:22]([O-])=[O:23].[Na+]>CN(C=O)C>[CH:22]([C:2]1[CH:3]=[C:4]([N:9]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8])=[O:23]
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(I)c1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(C=O)c1
Temperature: 100 °C

Procedure:
A mixture of N-(3-iodo-4-methylphenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (0.415 g, 0.997 mmol), sodium formate (0.102 g, 1.50 mmol), and dichloro-bis(triphenylphosphine)palladium (0.014 g, 0.020 mmol) were combined in 1.0 mL DMF and purged with anhydrous CO gas. The mixture was heated to 100° C. for 1.5 h. The reaction was poured into saturated NaHCO3 solution and extracted with EtOAc. The combined fractions were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The mixture was chromatographed on silica gel with 1:1 EtOAc/DCM to give the title compound as a clear oil. 1H NMR: 10.11 (s,1H), 8.38 (br s,1H), 8.26 (br s,1H). 7.60 (m,2H), 7.13 (m,1H), 7.00 (s,2H), 4.80 (s,2H), 3.00 (q,J=7.3 Hz, 2H), 2.52 (s,3H), 2.35 (t,J=7.3 Hz, 3H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:18]=[C:17]([CH3:19])[C:14]([C:15]#N)=[C:13]([CH3:20])[CH:12]=1.C(C(C(C([O-])=O)O)O)([O-])=[O:22].[K+].[Na+]>C(Cl)Cl>[Br:10][C:11]1[CH:18]=[C:17]([CH3:19])[C:14]([CH:15]=[O:22])=[C:13]([CH3:20])[CH:12]=1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: Cc1cc(Br)cc(C)c1C#N
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DIBAL-H (1.0M in hexanes; 22.0 mL, 22.0 mmol) was added to a solution of 4-bromo-2,6-dimethylbenzonitrile (3.87 g, 18 mmol) in CH2Cl2 (50 mL) at 0° C., and the resulting mixture stirred at 25° C. for 3 h. Saturated aqueous sodium potassium tartrate solution (75 mL) was then slowly added, and the resulting mixture was stirred vigorously for 30 min. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-20% EtOAc/hexanes) furnished 4-bromo-2,6-dimethylbenzaldehyde as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[N+:7]([O-:9])=[O:8].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13](OB(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[N+:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1sccc1Br
Reactant: Cc1ccc(OB(O)O)cc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccsc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A mixture of 0.8 g of 3-bromo-2-nitrothiophene, 0.52 g of 4-tolylboric acid, 5 ml of a 2M-aqueous potassium carbonate solution, 2.5 ml of ethanol and 30 ml of toluene was stirred at room temperature for 30 minutes in a nitrogen atmosphere. Successively 0.15 g of Pd(PPh3)4 was added and refluxed by heating for 7 hours. After separating into two layers, the organic layer was washed with water and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.56 g (70% yield) of the product as a yellow crystal. 1H-NMR(CDCl3, δ value):2.42(3H, s), 7.01(1H, d, J=5.1), 7.25(2H, d, J=8.1), 7.37(2H, d, J=8.1), 7.47(1H, d, J=5.1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][C:16]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][N:19]=4)=[CH:30][N:29]=3)=[O:18])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: Cc1cc(CC(=O)O)cnc1-c1ccnc(F)c1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: Cc1cc(CC(=O)Nc2ccc(-c3cnccn3)cn2)cnc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the mixture of 2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)acetic acid 193-2 (50 mg, 0.2 mmol) and 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (36 mg, 0.2 mmol) in DCM (1 mL) was added N,N′-Diisopropylcarbodiimide (46 μL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours. The solvent was removed by rotary evaporation and the residue was dissolved in DMSO and then purified by reverse-phase HPLC to give 2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 199 as white solid. MS m/z 401.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ11.07 (s, 1H), 9.25 (d, 1H, J=1.6 Hz), 9.05 (m, 1H), 8.66 (m, 1H), 8.57 (d, 1H, J=2.4 Hz), 8.47-8.45 (m, 2H), 8.28 (d, 1H, J=5.2 Hz), 8.16 (d, 1H, J=8.8 Hz), 7.71 (d, 1H, J=1.6 Hz), 7.51-7.49 (m, 1H), 7.31 (s, 1H), 3.82 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][N:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[CH:14][CH:13]=2)[CH:6]=1)(=O)=O.[NH2:32][CH2:33][CH2:34][OH:35]>ClCCl>[OH:35][CH2:34][CH2:33][NH:32][C:5]1[N:10]=[CH:9][N:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[CH:14][CH:13]=2)[CH:6]=1
Reactant: CS(=O)(=O)c1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Reactant: NCCO
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2cc(NCCO)ncn2)cc1)Nc1cccc(C(F)(F)F)c1
Temperature: 110 °C
Yield: 53.5 %

Procedure:
A solution of 1-[4-(6-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (100 mg, 0.22 mmol) in dichloromethane (1 ml) and 2-aminoethanol (133 μl, 2.2 mmol) is sealed in a reaction tube and heated in the microwave at 110° C. for 15 minutes. The reaction mixture is evaporated and purified by preparative HPLC to yield 51 mg (53%) of a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].[C:26](Cl)(=[O:28])[CH3:27].CCN(C(C)C)C(C)C>>[N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][S:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]=2[NH:1][C:26](=[O:28])[CH3:27])(=[O:13])=[O:14])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 34.9 %

Procedure:
In a similar fashion using route 15 general procedure 30, 2-amino-N-(quinolin-8-yl)-4-trifluoromethyl-benzenesulfonamide (Example Compound 35) (50 mg, 0.14 mmol), acetyl chloride (9 μl, 0.14 mmol) and DIPEA (59 μl, 0.34 mmol) gave the title compound (20 mg, 36%) after purification by column chromatography with DCM/n-hexane (4:1) as the eluent.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1([C:17]([OH:19])=O)[C:12]([CH3:14])([CH3:13])[C:11]1([CH3:16])[CH3:15])#[N:9].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C@H:30]([NH2:32])[CH3:31].C(P(=O)(OCC)OCC)#N>ClCCl>[C:8]([C:10]1([C:17]([NH:32][C@@H:30]([C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[CH3:31])=[O:19])[C:11]([CH3:15])([CH3:16])[C:12]1([CH3:13])[CH3:14])#[N:9]
Reactant: CC1(C)C(C)(C)C1(C#N)C(=O)O
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)C1(C#N)C(C)(C)C1(C)C)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.8 %

Procedure:
0.61 g (6 mmol) of triethylamine was added to a solution of 1.0 g (6 mmol) of 1-cyano-2,2,3,3-tetramethylcyclopropane-1-carboxylic acid (cf. Org. Prep. Proced. Int. 5, (1973), 25-29) and 1.03 g (6 mmol) of (1 R)-1-naphth-2-ylethylamine in 50 ml of dichloromethane. At 10° C., 0.94 g of 93% pure diethyl cyanophosphonate (6 mmol) was then added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated using a rotary evaporator and then purified by silica gel chromatography (mobile phase: methyl tert-butyl ether:hexane=1:9, then 3:7). 1.9 g (99% yield) of the title compound were isolated as a white solid of melting point 169-1750° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][C:9](N)=[O:10]>[Ni]>[C:9](=[O:10])([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[NH2:8]
Reactant: NC(N)=O
Reactant: CCCCCCO
Agent: [Ni]
Product: CCCCCCOC(N)=O
Temperature: 130 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
A mixture of 918 parts of hexyl alcohol, 300 parts of urea and 14 parts of a cation exchanger which is commercially available under the registered name Amberlite 200 and, having been treated in accordance with Example (1 a), contains nickel, is heated to 130° C. whilst stirring. The temperature is then raised to 150° C. in the course of 6 hours and maintained thereat for a further 4 hours. After filtering off the exchanger, excess hexyl alcohol is distilled off under reduced pressure. 680 parts of hexyl carbamate (94% of theory) are obtained. Melting point= 56°-57° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]3)[NH:7][C:6]2=1.[O:24]=[C:25]1[NH:30][C:29]2[CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=[CH:34][C:28]=2[O:27][CH2:26]1>>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:35]([C:32]4[CH:33]=[CH:34][C:28]5[O:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=5[CH:31]=4)=[O:36])[CH2:19][CH2:18]3)[NH:7][C:6]2=1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N)CC1)CO3
Product: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CO4)CC1)CO3

Procedure:
The titled compound is prepared as an off-white solid following Scheme 5 and in analogy to Example 27 using trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexylamine and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][N:19]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:10]=3)[NH:14][C:13]2=[O:18])=[CH:30][CH:29]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Product: COc1ccc(NN=C2C(=O)Nc3ccc(C4=NNC(=O)SC4C)cc32)cc1
Yield: 90 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and 4-methoxyphenyl hydrazine and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:16]=[C:15](O)[NH:14][N:13]=1.CC1C=CC(S(O)(=O)=O)=CC=1>>[O:1]([CH2:8][CH2:9][O:10][C:15]1[CH:16]=[C:12]([NH2:11])[NH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(O)[nH]n1
Reactant: OCCOc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1cc(OCCOc2ccccc2)n[nH]1
Temperature: 130 °C
Reaction time: 11 h
Yield: 30.7 %

Procedure:
A mixture of 2-phenoxyethanol (56.1 g, 406 mmol), 3-amino-1H-pyrazol-5-ol (8.0648 g, 81.4 mmol) and TsOH (30.96 g, 162.8 mmol) was stirred at 130° C. under vacuum for 11 h. After cooled down to room temperature, the solid was washed with MeCN (200 mL), then treated with 6% aqueous NaHCO3 solution (500 mL). The suspension was filtered, and the solid collected was dissolved in EtOAc (100 mL), dried over MgSO4, filtered and concentrated, giving the title compound (5.4734 g, 30.7% yield). ESI m/z=220.19 [(M+1)+; calcd for C11H13N3O2+H: 220.11].
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([C:14]2[CH:15]=[C:16]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:17]=[C:18]([C:20]([O:22]C)=[O:21])[CH:19]=2)[C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])C.O.O[Li].O>C1COCC1>[C:20]([C:18]1[CH:19]=[C:14]([N:9]2[C:10]([CH:11]([CH3:13])[CH3:12])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]2)[CH:15]=[C:16]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[CH:17]=1)([OH:22])=[O:21]
Reactant: CCOC(=O)c1nnn(-c2cc(C(=O)OC)cc(-c3ccc(C)cc3)c2)c1C(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnc(C(=O)O)c3C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 5-isopropyl-1-(5-methoxycarbonyl-4′-methyl-biphenyl-3-yl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester from step 1 was dissolved in THF (7 mL) and water (4 mL) and LiOH.H2O (184 mg, 4.38 mmol) were added as a single portion. The reaction mixture was stirred at room temperature for three hours. Solvent was removed under reduced pressure and the remaining aqueous solution was acidified with concentrated HCl to pH˜1. The solution was extracted with EtOAc and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-(5-carboxy-4′-methyl-biphenyl-3-yl)-5-isopropyl-1H-[1,2,3]triazole-4-carboxylic acid light yellow solid (260 mg), which was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[Br:8][CH2:9]CO.OS([O-])(=O)=O.[Na+]>C1(C)C=CC=CC=1>[Br:8][CH2:9][CH2:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1
Reactant: OCCBr
Reactant: COc1ccsc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: BrCCOc1ccsc1
Yield: 67 %

Procedure:
5.00 g of 3-methoxythiophene (Aldrich) was solubilized with 11.00 g of 2-bromoethanol in 20 mL of toluene, then 2.00 g of NaHSO4 was added in one portion. The mixture was heated and methanol was distilled off. The solution was cooled and washed with water and diethylether. The organic phase was dried with magnesium sulfate. After evaporation, a brown liquid was obtained which was purified by column chromatography on silica gel using a mixture of CCl4 and CHCl3 (9:1) as the eluent. An oil was recovered which was further purified by recrystallization in methanol. White crystals were then obtained with a yield of 67%. M.P.=46° C.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.Cl[C:25]1[N:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=1>>[OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][N:13]([C:25]3[N:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=3)[CH2:12]2)[CH2:6][CH2:5]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCNC2)C(=O)O1
Reactant: COc1cnc(Cl)nc1
Product: COc1cnc(N2CC[C@H](N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)C2)nc1
Reaction time: 0.33 h

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-pyrrolidin-3-yl)-1,3-oxazinan-2-one and 2-chloro-5-methoxypyrimidine following a procedure analogous to that described in Example 1 heating at 150° C. for 20 min. LC-MS Method 1 tR=1.27 min. min, m/z=427(M+1); 1H NMR (CD3OD) 8.17(d, 2H), 7.37(m, 5H), 4.79(m, 1H), 3.82(s, 3H), 3.67(m, 2H), 3.49(m, 1H), 3.78(m, 1H), 2.52(m, 2H), 2.24(m, 2H), 2.18(s, 2H), 1.24(s, 3H), 0.94(s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(I)cc1
Product: COc1ccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 85 %

Procedure:
(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxyphenyl)-1H-indol-3-yl)propanoic acid (1.12 g, 85%) was obtained from (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1-iodo-4-methoxybenzene using the procedure described for (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-methoxyphenyl)-1H-indol-3-yl)propanoic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.89-12.48 (m, 1H), 11.14 (s, 1H), 7.93-7.77 (m, 2H), 7.72-7.58 (m, 5H), 7.46-7.22 (m, 6H), 7.11-6.94 (m, 4H), 4.30 (dd, J=8.5, 6.0 Hz, 1H), 4.18-4.07 (m, 3H), 3.84-3.77 (s, 3H), 3.35 (m, 1H), 3.23-3.14 (m, 1H); [α]20D −9.44° (3.05 mg/mL, MeOH). LCMS retention time=1.810 min., m/z=533 (M+H), 97.3% purity. The LCMS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using The following set of conditions: PHENOMENEX® Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a flow rate of 1 mL/minute.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11]CC2C=CC(OC)=CC=2)[N:8]([CH2:21][C:22](=[O:38])[NH:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([CH2:21][C:22](=[O:38])[NH:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)n(CC(=O)N[C@H]2CCCC[C@@H]2OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)c1cc(O)n(CC(=O)N[C@H]2CCCC[C@@H]2OCc2ccccc2)n1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
An ice cold sample of 100 mg (0.192 mmol) of 1-[((1S, 2S)2-Benzyloxy-cyclohexylcarbamoyl)-methyl]-5-(4-methoxy-benzyloxy)-1H-pyrazole-3-carboxylic acid ethyl ester (2) was treated with 5 mL of 95:5 trifluoroacetic acid (TFA):H2O solution, and the resulting mixture was stirred for 1.5 h at rt, and then quenched by the addition of 5 mL of 1:1 acetonitrile:water solution. The mixture was concentrated to give 66 mg (86%) of crude 1-[((1S, 2S)2-benzyloxy-cyclohexylcarbamoyl)-methyl]-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (3) which was used without any further purification in the next reaction.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>C(O)CCC>[N:10]1([CH2:9][CH2:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCCCCCBr
Reactant: CC(CCN)c1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(CCN1CCCCC1)c1ccccc1-c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 2.25 g of 3-p-biphenylyl-butylamine, 1.38 g of potassium carbonate, 2.53 g of 1,5-dibromopentane and 15 ml of n-butanol is boiled for 24 hours, while stirring. The mixture is filtered and the filtrate is evaporated and worked up in the customary manner to give 1-piperidino-3-p-biphenylyl-butane.
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH:8]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].Cl>CN(C=O)C.O>[CH:14]1([CH:8]([C:25]2[CH:24]=[CH:23][C:22]([N+:27]([O-:29])=[O:28])=[C:21]([F:20])[CH:26]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)C(Cl)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
8.2 g of potassium tert-butylate were dissolved in 70 mL of DMF and cooled to −45° C. To this, a mixture of ethyl 2-chloro-2-cyclohexylacetate (36.6 mmol, 7.5 g) and 1-fluoro-2-nitrobenzene (36.6 mmol, 3.9 mL) was gently added dropwise and stirring was continued for a further 20 minutes. The reaction mixture was set to pH 4 with 16% strength aq. HCl, diluted with 25 mL of water, and extracted with EA (3×50 mL). After combining the organic phases, they were washed with water and sat. aq. NaCl solution, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EA in cyclohexane) and yielded 5.5 g (49%) of the desired product.