Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:18]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][C:29]([N:31]6[CH2:35][CH2:34][CH:33]([O:36]C7CCCCO7)[CH2:32]6)=[O:30])[CH:27]=5)[O:20][N:19]=4)[CH2:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:18]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][C:29]([N:31]6[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]6)=[O:30])[CH:27]=5)[O:20][N:19]=4)[CH2:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: Nc1ncc(-c2ccc(C3(c4noc(-c5cnn(CC(=O)N6CCC(OC7CCCCO7)C6)c5)n4)CCC3)cc2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1ncc(-c2ccc(C3(c4noc(-c5cnn(CC(=O)N6CCC(O)C6)c5)n4)CCC3)cc2)cn1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 39.7 %

Procedure:
R105 (65.0 mg, 0.114 mmol) is treated with ethanol (1.5 mL) and p-toluenesulfonic acid (5.7 mg, 0.20 mmol) and the resulting mixture is stirred at 60° C. for 2.5 hours. The reaction was cooled to room temperature and filtered. The resulting solid was purified by reverse-phase preparative HPLC eluting 10-90% acetonitrile/water/0.1% formic acid to give Example 239 (22.0 mg); m/z 487.4 [M+1].
Reaction SMILES: FC(F)(OC1C=CC(N)=CC=1)C(F)F.[F:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([N+:26]([O-])=O)[C:17]=1[N:29]1[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[N:31]=[CH:30]1>C(O)(C)C.O.Cl>[NH2:26][C:18]1[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=[C:16]([F:15])[C:17]=1[N:29]1[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[N:31]=[CH:30]1
Reactant: O=c1cc(C(F)(F)F)ncn1-c1c(F)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1ccc(OC(F)(F)C(F)F)cc1
Solvent: CC(C)O
Solvent: O
Product: Nc1cc(C(F)(F)F)cc(F)c1-n1cnc(C(F)(F)F)cc1=O
Temperature: 100 °C

Procedure:
4-Nitro-(1',1',2',2'-tetrafluoroethoxy-benzene was converted to 4-(1',1',2',2'-tetrafluoroethoxy)-aniline using the general procedure illustrated in Preparation 12 of EP 0 398 499. In such Preparation, reduced iron powder (0.18 g) was added to a suspension of 1-(2-fluoro-6-nitro-4-trifluoromethylphenyl)-4-trifluoromethylpyrimidin-6-one (0.6 g) in a mixture of isopropanol (6 ml) and water (0.6 ml). Concentrated hydrochloric acid (1 drop) was added, and the reaction mixture was heated to 100° C. for a period of 5 hours. After cooling to ambient temperature, the reaction mixture was filtered through celite, and the residue washed with ethyl acetate. Evaporation of the filtrate under reduced pressure gave 1-(2-amino-6-fluoro-4-trifluoromethylphenyl)-4-trifluoromethylpyrimidin-6-one.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C1(OC)C=CC=CC=1.C(N(CC)CC)C.[C:54](Cl)(=[O:62])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>FC(F)(F)C(O)=O.C1C=CC=CC=1.O1CCCC1.C(Cl)(Cl)Cl>[C:54]([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])[CH:10]([CH3:11])[CH3:12])(=[O:62])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: COc1ccccc1
Product: CCCCCCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of dibenzyl N-(N-tert-butoxycarbonyl-L-valyl)glutamate (1 g) and anisole (1 ml) in trifluoroacetic acid (2 ml) was stirred at 0° C. for 1 hour. Evaporation of trifluoroacetic acid under reduced pressure gave a residue which was taken up in benzene. Benzene was distilled off by using high vacuum pump. This operation was repeated three times to leave crude dibenzyl N-(L-valyl)-L-glutamate, which was dissolved in tetrahydrofuran (20 ml). To this solution was added triethylamine (1 ml) and n-octanoyl chloride (0.7 ml) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with chloroform and the organic layer was washed with 1N hydrochloric acid solution, aqueous sodium carbonate solution and brine successively, dried over magnesium sulfate. After solvent was evaporated, the residue was crystallized from ethyl acetate to afford white amorphous powder of dibenzyl N-(N-octanoyl-L-valyl)-L-glutamate (600 mg).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14]>>[CH3:10][CH:9]=[C:8]([NH:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)/C=C/c1ccccc1
Product: CC=C(Cc1ccccc1)NNC(=O)OC(C)(C)C

Procedure:
This compound was prepared by the method of Ghali et al. (J. Org. Chem., 1981, 46, 5413-5414) in about 65% overall yield, from trans-4-phenyl-3-buten-2-one and t-butyl carbazate, after crystallization of the crude product from hexane; melting point=76-79° C.; NMR (CDCl3) 1.24 (d, 3H, CH3); 1.45 (s, 9H, t-butyl CH3); 3.78 (m, 2H, propenyl CH-1, carbazate NH-3); 5.8-6.29 (m, 2H, carbazate NH-2, propenyl CH-2); 6.53 (d, 1H, propenyl CH-3); 7.3 (m, 5H, aromatic).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]1[C:7]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)#N.P(=O)(O)(O)[OH:23].C(O)(=O)C.C(OCC)(=O)C>O>[OH:12][C:8]1[CH:9]=[CH:10][C:11]2[C:1](=[O:23])[CH2:3][CH2:4][O:5][C:6]=2[C:7]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=P(O)(O)O
Reactant: N#CCCOc1cccc(O)c1CCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCOc2c1ccc(O)c2CCCc1ccccc1
Temperature: 125 °C

Procedure:
A mixture of 3.5 g (12.5 mmol) of 3-(2-cyanoethoxy)-2-(3-phenylpropyl)phenol (preceding example), 16 mL of 85% phosphoric acid, and 7.7 mL of acetic acid was stirred and heated at 125° C. for 23 hr. After being cooled, the mixture was diluted with water and worked-up with ethyl acetate in the usual manner giving 4 g of a red oil. This material was chromatographed on silica gel. Elution with hexane-ethyl acetate mixtures afforded 2.3 g (65.2%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[O:9])=[CH:5][CH:4]=1)[CH3:2].[H-].[Na+].[NH2:20]OC1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O>CN(C)C=O>[NH2:20][N:7]1[C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=[C:6]1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=1)=[O:9]
Reactant: CCc1ccc(C(=O)c2ccc(C#N)cc2)[nH]1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)c2ccc(C#N)cc2)n1N
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]-benzonitrile (12.5 g) in N,N-dimethylformamide (63 mL) was added 60% sodium hydride in oil (2.68 g) in an ice-water bath under N2. After 30 minutes, to the mixture was added 1-(aminooxy)-2,4-dinitrobenzene (13.3 g). After 2 hours, the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (100 mL) 3 times, 1N sodium hydroxide (100 mL), and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 500 mL) eluted with hexane-chloroform=1-2, 1-5, and 1-10 followed by triturated with isopropyl ether to give 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (8.1 g, 60.7%) as an yellow solid. The mixed fraction and the mother layer (7 g) were repurified by flash silica gel chromatography (silica gel, 200 mL) eluted with hexane-chloroform=2-1 and 1-1 followed by triturated with isopropyl ether to give 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (2.0 g, 15%) as a pale yellow solid.
Reaction SMILES: [Cu](C#N)C#N.[CH:6]([Mg]Br)([CH3:8])[CH3:7].[CH2:11]([O:13][C:14](=[O:36])[C:15](=[CH:21][C:22]1[CH:23]=[N:24][C:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][CH:27]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12].[Cl-].[NH4+]>O1CCCC1.N>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH:21]([C:22]1[CH:23]=[N:24][C:25]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:26][CH:27]=1)[CH:6]([CH3:8])[CH3:7])[C:14]([O:13][CH2:11][CH3:12])=[O:36])[CH3:20]
Reactant: CC(C)[Mg]Br
Reactant: CCOC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Agent: N#C[Cu]C#N
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(c1ccc(NC(=O)OC(C)(C)C)nc1)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
To a stirred solution of copper cyanide (3.58 g, 40 mmol) in tetrahydrofurane (50 mL) at −15° C. a solution of isopropylmagnesium bromide (40 mL, 2 M, 80 mmol) in tetrahydrofurane was added under argon over 15 min. After additional 15 min stirring a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethylene)-malonic acid diethyl ester (3.78 g, 10.4 mmol) in tetrahydrofurane (50 ml) was added dropwise over 15 min. After stirring for 16 h the mixture was allowed to warm up to room temperature. Then a solution of ammonium chloride (5%) in aqueous ammonia solution (5%) was added with vigorous stirring, allowing access of air. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed successively with aqueous ammonia solution (5%) and brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 1.7% methanol in dichloromethane) to give crude 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propyl]-malonic acid diethyl ester (2.85 g, 25%).
Reaction SMILES: I[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[H-].[Na+]>CN(C)C=O>[CH3:9][C:7]1[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:2][CH2:3][N:4]2[CH:8]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cn2c1C(C(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 1-(2-iodoethyl)-3-carboethoxy-4-methyl-pyrrole-2-acetate in 65 ml of dry dimethylformamide was treated with 1.6 g NaH (60% in mineral oil) and stirred for 60 minutes at room temperature. The mixture was quenched with 100 ml of water and extracted with ethylacetate (3×100 ml). The ethyl acetate layer was washed with water, dried over MgSO4, filtered and evaporated to dryness to yield 6.4 g of crude diethyl 1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylate to be used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](OC)=[O:11].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: COC(=O)c1cc2cccnc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To an ice-cold solution of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (300 mg) in THF (4.5 mL) was added LiAlH4 (1.7 mL, 1M in THF). The ice bath was removed and the reaction mixture was stirred at RT for 2 h. LiAlH4 (2.8 mL, 1M in THF) was added and the stirring was pursued for 20 h at RT. DCM and 1M NaOH were added and the phases were separated. The org. layer was dried (Na2SO4) and evaporated in vacuo to afford 100 mg of oil. LC-MS (B): tR=0.34 min; [M+H]+: 149.28.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C([CH2:15][S:16]([CH2:19][S:20]([CH2:23][C:24](O)=O)(=[O:22])=[O:21])(=[O:18])=[O:17])(O)=O>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])/[CH:5]=[CH:15]/[S:16]([CH2:19][S:20](/[CH:23]=[CH:24]/[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([OH:1])[CH:3]=1)(=[O:21])=[O:22])(=[O:17])=[O:18]
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: COc1ccc(C=O)cc1O
Solvent: CC(=O)O
Product: COc1ccc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2ccc(OC)c(O)c2)cc1O
Yield: 62 %

Procedure:
A solution of 3-hydroxy-4-methoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 62% yield. m.p. 148-150° C.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[N:6]=[CH:5][C:4]([C:3]([N:26]4[CH2:31][CH2:30][S:29][CH2:28][CH2:27]4)=[O:25])=[CH:9][CH:8]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: C1CSCCN1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cn3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 59 %

Procedure:
As described for example 301, [6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (108 mg, 0.3 mmol) was converted, using thiomorpholine instead of 4-aminotetrahydropyran to the title compound (76 mg, 59%) which was obtained as a white solid. MS: m/e=431.3 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH:33]([OH:37])[CH2:32]1)[CH3:30]>C1(C)C=CC=CC=1.[Cu]I.CCOC(C)=O.O>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([O:37][CH:33]2[CH2:34][CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32]2)=[CH:24][CH:23]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCN1CCCC(O)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN1CCCC(Oc2ccc(Br)cc2)C1
Temperature: 110 °C
Reaction time: 36 h

Procedure:
652 mg (2.00 mmol) caesium carbonate, 36 mg (0.20 mmol) 1,10-phenanthroline and 19 mg (0.10 mmol) CuI are added to a solution of 289 mg (1.00 mmol) 1-bromo-4-iodobenzene and 0.27 mL (2.00 mmol) N-ethyl-3-hydroxypiperidine in 1.0 mL toluene. The reaction mixture is stirred for 36 h at 110° C. and then combined with 10 mL water and 10 mL EtOAc. After filtration the aqueous phase is extracted with 10 mL EtOAc and the combined organic extracts are washed with saturated NaCl solution and dried over Na2SO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][O:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH:39]([CH2:42][NH:43][CH3:44])[CH2:38]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:43]([CH2:42][CH:39]5[CH2:40][CH2:41][N:37]([CH2:36][CH2:35][O:34][CH3:33])[CH2:38]5)[CH3:44])=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:32])[F:30])[CH:3]=1
Reactant: CNCC1CCN(CCOC)C1
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COCCN1CCC(CN(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-{[1-(2-methoxy-ethyl)-pyrrolidin-3-ylmethyl]-methyl-amino}-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and [1-(2-Methoxy-ethyl)-pyrrolidin-3-ylmethyl]-methyl-amine following General Procedure B.
Reaction SMILES: Cl.[F:2][C:3]([F:10])([F:9])[CH2:4][C:5]([NH2:8])([CH3:7])[CH3:6].[N-:11]([C:14]#[N:15])[C:12]#[N:13].[Na+]>C(O)CCC>[C:12]([NH:11][C:14]([NH:8][C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([F:10])([F:9])[F:2])=[NH:15])#[N:13]
Reactant: N#C[N-]C#N
Reactant: CC(C)(N)CC(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)(CC(F)(F)F)NC(=N)NC#N
Yield: 82.3 %

Procedure:
A mixture of 3,3,3-trifluoro-1,1-dimethylpropylamine hydrochloride (2.67 g, 15 mol), sodium dicyanamide (1.34 g, 15 mmol), and n-butanol (7.5 ml) was sealed in vacuo in a Pyrex ampoule and was heated at 105° for 119 h to give, after solvent removal, a residue (2.87 g) which was crushed and stirred with water (7 ml), then filtered and washed with water, then dried to give a solid (2.57 g) with m.p. 153° (shrinks 145°). The solid was dissolved in methanol (25 ml) then filtered to remove what is presumed to be polymeric dicyanamide (0.06 g). Removal of solvent and drying gave the guanidine (2.35 g) m.p. 153°-4°.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:46])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:36])=[C:32]([Cl:35])[CH:33]=5)[N:28]([CH3:37])[N:27]=4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:46])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:36])=[C:32]([Cl:35])[CH:33]=5)[N:28]([CH3:37])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c2cc(Cl)c(Cl)cc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C4CC4)c3n2)c2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
To a solution of 2-(5,6-dichloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (130 mg, 0.19 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL, 26.0 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (4 mL) and ethylenediamine (0.4 mL, 5.92 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h then quenched with water and extracted with CH2Cl2 (3×). The combined organics were concentrated. The residue was purified by silica gel chromatography with 0% to 4% MeOH/CH2Cl2 (0.5% NH4OH) followed by trituration with Et2O to afford a white solid. This solid was further purified by recrystallization from MeOH/EtOAc to afford 22 mg of 2-(5,6-dichloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a white solid. MS: (M+Na)+=573; 1H NMR (DMSO-d6,300 MHz): δ (ppm) 12.92 (br. s., 1H), 9.14 (s, 1H), 8.88 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.46 (d, J=8.7 Hz, 1H), 8.24 (s, 1H), 4.93 (t, J=7.4 Hz, 1H), 4.18 (s, 3H), 3.45-3.94 (m, 3H), 3.15 (d, J=4.9 Hz, 2H), 1.35-1.91 (m, 5H), 0.51 (br. s., 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1>C(O)C.C(Cl)Cl.[Pt](=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[CH:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1
Reactant: CN1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCO
Product: CN1CCC(c2cc(C(F)(F)F)ccc2Br)CC1
Reaction time: 1 h
Yield: 2.36 %

Procedure:
4-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine was dissolved in 20 mL ethanol and the solution was treated with platinum (iv) oxide (0.194 g, 0.854 mmol), and was placed under 45 psi H2 for one hour. LC/MS showed product and debrominated product, so the reaction mixture was diluted with DCM, filtered through a plug of diatomaceous earth and was concentrated. Purification of the crude residue by silica gel column chromatography (0 to 97% EtOAc/heptane, 3% MeOH) gave 4-(2-bromo-5-(trifluoromethyl)phenyl)-1-methylpiperidine (0.065 g, 0.202 mmol, 2.363% yield). m/z (ESI) 322.0 (M+Na)+;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][C:57]([O:59][CH3:60])=[O:58]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][CH2:56][C:57]([O:59][CH3:60])=[O:58])=[CH:13][CH:12]=1
Reactant: COC(=O)CCc1ccccc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COC(=O)CCc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method F, 0.30 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and methyl 3-(2-hydroxyphenyl)propionate are used to prepare the title compound as a colourless oil. Rf=0.23 (1:2 EtOAc-heptane); Rt=6.20.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[CH3:12]N(P(N(C)C)(N(C)C)=O)C.[Li+].CC([N-]C(C)C)C.CI>C1COCC1>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])[N:6]=1
Reactant: COC(=O)Cc1coc(C)n1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1coc(C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To the intermediate from Step A (1.35 g, 8.71 mmol) and HMPA (6.24 g, 34.8 mmol) in 10 mL of THF at −78° C. was added dropwise a LDA solution (2.0 M, 5.22 mL, 10.5 mmol). The mixture was stirred at −78° C. for 30 min and MeI (1.48 g, 10.45 mmol) was added dropwise. The resulting mixture was slowly warmed to room temperature. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (yellow oil). 1H NMR (CDCl3, 500 MHz) δ 7.48 (1H, s), 3.77 (3H, s), 3.76 (1H, q, J=7.5 Hz), 2.49 (3H, s), 1.55 (3H, d, J=7.5 Hz).
Reaction SMILES: [OH-].[K+].Cl.NO.CC1[N:8]([C:13]2[CH:21]=[C:16]3[CH2:17]N[CH2:19][CH2:20][N:15]3[N:14]=2)C(C)=CC=1.[CH2:22](O)C>O>[NH2:8][C:13]1[CH:21]=[C:16]2[CH2:17][CH2:22][CH2:19][CH2:20][N:15]2[N:14]=1
Reactant: Cc1ccc(C)n1-c1cc2n(n1)CCNC2
Reactant: CCO
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Product: Nc1cc2n(n1)CCCC2
Reaction time: 0.25 h

Procedure:
8.19 g (146 mmole) potassium hydroxide, dissolved in 122 ml water and 122 ml ethanol, was added to 19.19 g (292 mmole) hydroxylamine hydrochloride in 200 ml ethanol. The mixture was stirred for 15 minutes, 12.5 g (58 mmole) 2-(2,5-dimethyl-1-pyrrolyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine added and heated for 30 hours under reflux. After removal of the ethanol the mixture was treated with ethyl acetate, filtered from solid material and the aqueous phase saturated with sodium chloride and extracted with ethyl acetate. The organic phase was with washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/methanol).