Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[S-2:16].[Na+].[Na+].Cl>CN(C=O)C>[SH:16][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: [S-2]
Reactant: N#Cc1ccc(-c2ccncc2F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccncc2S)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 4-(3-fluoropyridin-4-yl)benzonitrile (1.08 g, 5.4 mmol) and sodium sulfide (0.84 g, 10.8 mmol) in DMF (20 mL) was stirred at 130° C. for 0.5 hours. While the reaction was cooled in ice water bath, aqueous HCl (6N, 2.5 mL) was added drop wise with rigorous stirring. The resulting yellow paste was concentrated using rotary evaporation on a water bath (80° C.) to dryness. The resulting yellow solid was extracted with methanol (4×20 mL). The combined extracts were concentrated to dryness to give a yellow solid (1.1 g, 96%).
Reaction SMILES: [CH3:1][Si:2]([CH3:56])([CH3:55])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])([C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35])[CH2:30][CH2:29]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:62]([O:64][CH2:65][CH3:66])=[CH2:63])CCC>O1CCOCC1.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>[CH3:1][Si:2]([CH3:56])([CH3:55])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])([C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35])[CH2:30][CH2:29]2)[C:9]=1[C:62]([O:64][CH2:65][CH3:66])=[CH2:63]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COCCOC(=O)C1(OCCOC)CCC(c2nc3c(-c4cnn(-c5ccccc5)c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C2CCC(OCCOC)(C(=O)OCCOC)CC2)nc2c(-c3cnn(-c4ccccc4)c3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A mixture of 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate (300 mg, 0.343 mmol), tributyl(1-ethoxyvinyl)tin (0.348 mL, 1.03 mmol), Pd(PPh3)4 (39.6 mg, 0.034 mmol) in dioxane (3.5 mL) was stirred at 100° C. under Ar for 16 h. The reaction mixture was passed through a short SiO2/KF (9:1) plug (eluting with EtOAc) to remove the majority of Tin species. After evaporating, the crude product was purified by a SiO2 column (0-30%, EtOAc/Hexanes, Rf=0.65 in 50% EtOAc) to afford 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate as a pale yellow oil (258 mg, 87%).
Reaction SMILES: CC1C=CC(C[C:7]2[CH:15]=[C:14]([C:16](O)=[O:17])[C:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=CC=1.FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:9][C:8]1[CH:7]=[CH:15][C:14]2[CH2:16][C:7]3[C:8]([C:9](=[O:11])[C:13]=2[CH:12]=1)=[CH:12][C:13]1[CH2:19][C:20]2[C:21](=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:16](=[O:17])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)C(=O)c1cc3c(cc1C2)C(=O)c1cc(C)ccc1C3
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 12.7 grams of 2,5-bis(4-methylbenzyl)terephthalic acid and 90 mL of trifluoroacetic acid was added 81.6 grams of trifluoromethanesulfonic acid. The reaction was stirred 22 hours at room temperature. The mixture was poured over 500 grams of ice. The resulting solid precipitate was collected by filtration, washed with 750 mL of saturated aqueous sodium bicarbonate and 1 L of water until the filtrate was neutral to pH paper. The solid was washed with heptane and dried to give 7,14-dihydro-3,10-dimethylpentacene-5,12-dione.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[S:15][C:14]([S:16][CH3:17])=[C:13]([S:18]([C:21]2[CH:22]=[C:23]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([O:34]C)=[CH:29][C:28]=3[CH2:36][O:37][CH2:38][C:39]([OH:41])=[O:40])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH:12]=1)(=[NH:10])[NH2:9].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[S:15][C:14]([S:16][CH3:17])=[C:13]([S:18]([C:21]2[CH:22]=[C:23]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([OH:34])=[CH:29][C:28]=3[CH2:36][O:37][CH2:38][C:39]([OH:41])=[O:40])[CH:24]=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH:12]=1)(=[NH:9])[NH2:10]
Reactant: COc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)N)sc3SC)c2)c(COCC(=O)O)c1
Agent: BrB(Br)Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cc(O)cc2COCC(=O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of [3′-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-methoxy-6-methyl-biphenyl-2-ylmethoxy]-acetic acid ((Example 192: step g) 0.077 g, 0.0148 mmol) in dry CH2Cl2 (10 mL) was cooled to 0° C. and treated with BBr3 (0.592 mL, 0.592 mmol) dropwise. The reaction stirred at 0° C. for 30 min. then was allowed to warm to room temperature and stir 27 h. The reaction mixture was cooled to 0° C. and quenched with MeOH. Some HBr evolution was seen. All solvents were evaporated in vacuo, and the residue was taken up in EtOAc (100 mL) and washed with water (1×75 mL) and brine (2×50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Preparatory HPLC (5–50% acetonitrile in 1% TFA/water over 30 min.) afforded the product [3′-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-hydroxy-6-methyl-biphenyl-2-ylmethoxy]-acetic acid trifloroacetate (0.039, 52%) as a white glassy solid. 1H NMR (MeOD): δ 8.344 (s, 1H), 8.090 (d, 1H, J=8.0 Hz), 7.877 (t, 1H, J=2.0 Hz), 7.721 (t, 1H, J=7.6 Hz), 7.572 (d, 1H, J=7.6 Hz), 6.778 (d, 1H, J=2.8 Hz), 6.735 (d, 1H, J=2.0 Hz), 2.710 (s, 3H), 2.028 (s, 2H), 1.935 (s, 3H), 1.254 (t, 2H, J=7.6 Hz).
Reaction SMILES: [C:1]([N:4]([CH2:6][C:7]([OH:9])=[O:8])[CH3:5])(=O)C.[P:10]([OH:13])([OH:12])[OH:11].S(=O)(=O)(O)O.C=O>O>[P:10]([CH2:1][N:4]([CH3:5])[CH2:6][C:7]([OH:9])=[O:8])([OH:13])([OH:12])=[O:11]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: OP(O)O
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(CC(=O)O)CP(=O)(O)O
Temperature: 120 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
N-acetyl sarcosine (XX) (2.0 g, 15.3 mmole), phosphorous acid (1.25 g, 15.3 mmole) were mixed with concentrated sulfuric acid (3.1 g) and water (1.7 g) then refluxed in a 120° C. oil bath. Formalin, 37% (1.4 g, 16.7 mmole) was added dropwise over 20 min. and the reaction was continued for an additional 18 h. 31 p NMR analysis indicated 98% yield of (XXI) based on mmoles of (XX) charged.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2c3c(sc2n1)CCCC3
Reactant: c1nc[nH]n1
Product: c1ncn(-c2nc(NCc3ccc4c(c3)OCCO4)c3c4c(sc3n2)CCCC4)n1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1.C[O:18][C:19]([NH:21][NH2:22])=[S:20]>C1(C)C=CC=CC=1>[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]2[CH2:2][S:20][C:19](=[O:18])[NH:21][N:22]=2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: COC(=S)NN
Reactant: CC(=O)Nc1ccc(C=CC(=O)CCl)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C=CC2=NNC(=O)SC2)cc1

Procedure:
A mixture containing 4.0 g of 1-chloro-4-(4-acetamidophenyl)-2-oxo-3-butene (J. Org. Chem., 28, 2446, 1963) and 2.3 g of hydrazinecarbothioic acid O-methylester in 150 ml of toluene was refluxed for 3 h. The crystals were filtered and washed with toluene. Yield 3.0 g (65%), mp. 235°-240° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:23]1([CH2:22][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CN(Cc2ccccc2)C2CCNCC2)cc1
Reaction time: 3 h
Yield: 100 %

Procedure:
1,1-Dimethylethyl 4-[bis(phenylmethyl)amino]-1-piperidinecarboxylate D74 (160 g, 420 mmol) was dissolved in dichloromethane (DCM) (1 L) and TFA (188 mL, 2443 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 3 h then further 100 mL of TFA was added and stirred for 2 h. The mixture was concentrated under reduced pressure and the residue treated with saturated solution NaHCO3 (1.5 L) and NaOH (3M solution; 200 mL) to basic pH. The aqueous phase was extracted with DCM (2×1.5 L). Combined organic layers were diluted with ethyl acetate (100 mL), washed with water (1×1 L) and brine (1×1 L) then dried on Na2SO4 and concentrated to obtain title material (118 g; 100%).
Reaction SMILES: C[O:2][C:3]1[C:4]2[C:9]([C:10]3[CH:11]=[CH:12][CH2:13][C:14](=O)[C:15]=3[CH:16]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.B(Br)(Br)Br.C[OH:23]>C(Cl)Cl>[OH:2][C:3]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:23]
Reactant: COc1cc2c(c3ccccc13)C=CCC2=O
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCCc2c(O)cc3c(c21)CCCC3
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
47.4 g (0.22 mol) of the 9-methoxy-phenanthrenone from Example 3 are dissolved in 605 ml of absolute methylene chloride and 440 ml of a 1 molar solution of boron tribromide in methylene chloride are added dropwise at -78° C. The mixture is stirred at -78° C. for 0.5 h, then at +20° C. for 3 h, cooled again to -78° C. and 620 ml of methanol is slowly added. The mixture is allowed to come to 20° C. and is evaporated. The residue is partitioned between 200 ml of CH2Cl2 and 200 ml of 1N NaOH solution, and the NaOH phase is separated and acidified to pH 1 using concentrated HCl solution with ice cooling. The precipitate is filtered off and dried in a high vacuum.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[N:16]=[CH:15][N:14]=[C:10]3[N:11]=[CH:12][NH:13][C:9]=23)[O:4][CH:5]=1.Br[CH2:18][CH2:19][Cl:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:6]([NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:10]2[C:9]=1[N:13]=[CH:12][N:11]2[CH2:18][CH2:19][Cl:20])[C:3]1[O:4][CH:5]=[CH:1][CH:2]=1
Reactant: ClCCBr
Reactant: c1coc(CNc2ncnc3nc[nH]c23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: ClCCn1cnc2c(NCc3ccco3)ncnc21
Yield: 80 %

Procedure:
Kinetin (2 g, 9.3 mmol), 1-bromo-2-chloroethane (1.3 g, 9.1 mmol) and K2CO3 (2.5 g, 24 mmol) were mixed in 100 ml dimethylsulfoxide (DMSO) for 18 h. The reaction mixture was poured onto 200 ml drift ice and then extracted in ethyl acetate and dried over Na2SO4. The ethyl acetate layer was evaporated in vacuo. The pure product of white powder character was recrystallised from methanol. Yield: 80%. 1H NMR (DMSO-d6): 4.07 (2H, t, J=5.82), 4.52 (2H, t, J=5.82), 4.70 (2H, s (br)), 6.23 (1H, d, J=2.67), 6.35 (1H, m), 7.53 (1H, d, J=2.67), 8.22 (2H, m), 8.25 (1H, s)
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.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>[F:8][C:3]1[C:2]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Fc1ncccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Fc1ncccc1-c1ccncc1

Procedure:
To a 50 mL round-bottomed flask was added 3-bromo-2-fluoropyridine (1.0135 g, 5.759 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.4577 g, 7.141 mmol), and trans-dichlorobis(triphenylphosphine)palladium(ii) (0.2138 g, 0.2879 mmol) in 1,2-dimethoxyethane. An aqueous solution of cesium carbonate (1.567 mL, 15.55 mmol) was added and the temperature was brought to 80° C. The reaction was monitored by LCMS to completion. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (1×10 mL), satd sodium chloride solution (1×10 mL), dried with magnesium sulfate, filtered, and concentrated. The solid was washed with ether and filtered to give 2-fluoro-3-(pyridin-4-yl)pyridine.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1([CH2:25][OH:26])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]1=[O:24].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[C:10]3([CH2:25][O:26][C:2]=2[CH:7]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24]
Reactant: CCCCCN1C(=O)C(CO)(c2ccc(OC)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3cc(OC)ccc32)c2ccccc21
Yield: 99 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(2-hydroxy-4-methoxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 99% yield: 1H NMR (300 MHz, CDCl3) δ 7.30 (td, 1H), 7.14 (dd, 1H), 7.03 (t, 1H), 6.91 (d, 1H), 6.58 (d, 1H), 6.52 (d, 1H), 6.36 (dd, 1H), 4.93 (d, 1H), 4.69 (d, 1H), 3.91-3.63 (m, 2H), 3.77 (s, 3H), 1.81-1.65 (m, 2H), 1.46-1.29 (m, 4H), 0.91 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.4, 162.1, 161.5, 142.5, 132.9, 128.8, 123.9, 123.5, 123.1, 121.0, 108.5, 107.5, 96.6, 80.5, 57.6, 55.6, 40.3, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 338 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C)[C@@H:9](C)C(N[C@@H](C(C)C)C(N1C2C(=CC=CC=2)C[C@H]1C(O)=O)=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 221.9 %

Procedure:
(S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-indole-2-carboxylic acid (60 mg, 134 μmol, Eq: 1) and EDC (77.1 mg, 402 μmol, Eq: 3) and HOAT (54.7 mg, 402 μmol, Eq: 3) were stirred in DMF (6 mL) for 10 min to give a light yellow solution. To this solution was added ammonium chloride (71.7 mg, 1.34 mmol, Eq: 10) and diisopropylethylamine (0.47 μL, 2.68 mmol, Eq: 20) in 2 mL of DMF. The mixture was stirred at rt overnight, and then concentrated in vacuo. The reaction mixture was poured into saturated aqueous NaHCO3 (30 mL) and extracted with DCM (2×20 mL). The organic layer was washed with 0.5 M aqueous citric acid and brine, and then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 90% EtOAc in hexanes) to afford {(S)-1-[(S)-1-((S)-2-carbamoyl-2,3-dihydro-indole-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl})-methyl-carbamic acid tert-butyl ester as an off-white powder (39 mg), m/z=447 (M+H).
Reaction SMILES: NC1C(F)=CC(Cl)=C(O[C:9](=O)[O:10][C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([F:18])=[CH:13][C:12]=2[Cl:19])C=1.[CH2:23](Br)[C:24]#C.[OH-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:19][C:12]1[C:11]([O:10][CH2:9][C:23]#[CH:24])=[CH:16][C:15]([NH2:17])=[C:14]([F:18])[CH:13]=1
Reactant: Nc1cc(OC(=O)Oc2cc(N)c(F)cc2Cl)c(Cl)cc1F
Reactant: C#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCOc1cc(N)c(F)cc1Cl
Temperature: 80 °C
Yield: 184.1 %

Procedure:
A round-bottomed flask (50 cc) was charged with bis(5-amino-2-chloro-4-fluorophenyl)carbonate (1.53 g, 4.39 mmol), propargyl bromide (1.11 g, 9.36 mmol) and tetrabutylammonium bromide (70 mg, 0.22 mmol) to prepare a solution in toluene (10 mL). Subsequently, 48% sodium hydroxide in aqueous solution (5 mL) was added slowly and the mixture was stirred under heating at 80° C. for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (15 mL) was added, followed by extraction with toluene (10 mL×2). The organic layers were combined and washed with water (10 mL×2). The solvent was distilled off under vacuum from the resulting toluene solution, thereby giving 4-chloro-2-fluoro-5-propargyloxyaniline (1.61 g, 8.08 mmol; yield=92.0%). 1H-NMR(CDCl3,TMS,ppm): δ2.54(1H,t,J=2.3Hz), 3.79(2H,brs), 4.70(2H,d,J=2.3Hz), 6.58(1H,d,JHF =8.9Hz), 7.07(1H,d,JHF =11.2Hz).
Reaction SMILES: [C:1](=O)=O.[CH:4]1([C:7]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:8]=2)[CH2:6][CH2:5]1.C[Mg]Br>C1COCC1.CCOCC>[CH:4]1([C:7]2[C:12]([CH:13]([OH:14])[CH3:1])=[CH:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[N:8]=2)[CH2:6][CH2:5]1
Reactant: O=C=O
Reactant: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a dry ice chilled solution of 0.75 g (2.57 mmol) 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbaldehyde in 5 ml THF was dropped a solution of 1.11 ml (3.33 mmol) 3M methylmagnesium bromide in 2.5 ml THF. The reaction mixture was allowed to warm to RT and it was stirred for 15 min at this temperature. The reaction mixture was then taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/dichloromethane 1:6, to give 384 mg of pure [rac]-1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethanol.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH2:25]([N:15]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(CN(Cc2ccccc2)c2cc(-c3ccncc3)cc3nc(-c4ccccc4)nn23)cc1
Reaction time: 70 h
Yield: 73.3 %

Procedure:
A solution of 0.20 g (0.0007 mol) 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine in 17.5 ml dimethylsulfoxide was treated with 0.69 g (0.01 mol) potassiumhydroxide(85%) for 20 minutes at room temperature. Then 0.26 g (0.0015 mol) benzylbromide were added and stirring was continued for 70 hours. Saturated aqueous sodiumbicarbonate was added and the mixture was extracted with chloroform. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 98/2 and crystallisation from diethylether gave 0.12 g (44%) dibenzyl-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-amine as light brown crystals. MS m/e (%): 468 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[NH3:13]>CO>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:13])[CH:7]=1
Reactant: N
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Solvent: CO
Product: Nc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (1.50 g, 6.30 mmol) and 7M ammonia in methanol (25 mL) was heated in a sealed tube at 60° C. for 15 h. The reaction mixture was transferred to a round bottom flask, washing the sealed tube with EtOAc. The reaction mixture was concentrated, and the crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCOCC4)c3)n2)n1
Yield: 75.6 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.300 g, 0.613 mmol) by treatment with morpholine (0.160 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.250 g, 75%) as a white solid. MS (ISP) 540.3 [(M+H)+]; mp 216° C.