Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]21[C:10]1[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:9]=1[S:8](=[O:19])(=[O:18])[CH2:7][CH2:6]2.C(Cl)(=O)C(Cl)=O.[C:26]1(=O)[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH2:27]1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][C:2]21[C:10]1[CH:11]=[C:12]([C:15]([O:17][C:26]3[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH:27]=3)=[O:16])[CH:13]=[CH:14][C:9]=1[S:8](=[O:19])(=[O:18])[CH2:7][CH2:6]2
Reactant: O=C(O)c1ccc2c(c1)C1(CCS2(=O)=O)OCCO1
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=C(OC(=O)c2ccc3c(c2)C2(CCS3(=O)=O)OCCO2)CCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
2.0 g (7.0 mmol) of the title compound of Step E, 1.2 mL (0.014 mol) of oxalyl chloride (purchase from Janssen), and 2 drops of N,N-dimethylformamide were added to 50 mL of methylene chloride. The mixture was refluxed under nitrogen for 2 h, and was then evaporated to dryness. 50 mL of methylene chloride was added to the residue and the resulting mixture was evaporated to dryness. Another 50 mL of methylene chloride was added to the residue, and the solution was cooled to about 0° C. 0.86 g (7.7 mmol) of 1,3-cyclohexanedione (purchased from Aldrich Chemical Company) was added followed by 2.7 mL (0.0196 mol) of triethylamine, and the mixture was stirred overnight while warming to room temperature. The mixture was evaporated to dryness, the residue was stirred in 100 mL of water and filtered. The crude product was washed with hexane to yield 2.19 g of the title compound of Step F as a solid melting at 185-186° C. 1H NMR (CDCl3): δ2.2 (m,2H), 2.5 (t,2H), 2.7 (t,4H), 3.7 (m,2H), 4.2 (m,2H), 4.3 (m,2H), 6.0 (s,1H), 8.0-8.25 (3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:20])[CH2:12][S:13][CH2:14][C:15]1[O:19][CH:18]=[CH:17][CH:16]=1.C([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])C.S(Cl)(Cl)=O.[CH:35](Cl)(Cl)Cl>>[N:26]1([CH2:2][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:20])[CH2:12][S:13][CH2:14][C:15]2[O:19][CH:18]=[CH:17][CH:16]=2)[CH2:27][CH2:28][CH2:35][CH2:30][CH2:29]1
Reactant: CCN(CC)CC
Reactant: ClC(Cl)Cl
Reactant: O=C(CSCc1ccco1)NCCCOc1cccc(CO)c1
Solvent: O=S(Cl)Cl
Product: O=C(CSCc1ccco1)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 3 h
Yield: 65.3 %

Procedure:
N-[3-(3-hydroxymethylphenoxy)propyl]-2-(furfurylthio)acetamide (6.5 g) and triethylamine (4 g) were dissolved in 200 ml of chloroform. Under ice cooling, 2.8 g of thionyl chloride was added dropwise to the solution. The mixture was stirred for 3 hours, and then the solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried. The solvent was evaporated, and the residue was dissolved in 250 ml of ethanol and refluxed with 5 g of piperidine. Five hours later, the reaction solution was concentrated. The residue was taken into ethyl acetate and washed with 5% HCl. The washing (aqueous layer) was made alkaline with potassium carbonate (solid), and again extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to give 5.09 g (yield 65.3%) of N-(3-[3-(piperidinomethyl)phenoxy]propyl)-2-(furfurylthio)acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[F:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>>[F:19][C@@H:20]1[CH2:24][CH2:23][N:22]([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:21]1
Reactant: F[C@@H]1CCNC1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N3CC[C@@H](F)C3)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18) and (R)-3-fluoropyrrolidine. m/z 324.
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([O:18]CC)=[O:17])[C:12]=2[CH3:21])=[CH:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>C1COCC1.C(O)C>[CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[C:12]=2[CH3:21])=[CH:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1noc(C2=CCC(OC(C)C)CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)noc1C1=CCC(OC(C)C)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of [ethyl 5-(4-isopropoxycyclohex-1-en-1-yl)-4-methylisoxazole-3-carboxylate] (393 mg, 1.340 mmol) in THF (3 mL) and Ethanol (3 mL), 2M NaOH (aq) (4.179 ml, 8.36 mmol) was added. The reaction mixture was stirred at room temperature. Upon completion the resulting mixture was poured into water (20 mL) and the pH adjusted to pH 6 with the addition of 1M HCl (aq). The aqueous was extracted with EtOAc (30 mL) and the organic extracts were washed with brine (20 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13][C:14]1[C:15]([NH2:23])=[C:16]([NH2:22])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1.[CH3:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=1.[Cl:36]N1C(=O)CCC1=O>>[NH2:22][C:16]([CH3:24])([CH2:17][N:9]1[N:10]=[C:6]2[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=[C:2]([Cl:1])[C:7]2=[N:8]1)[C:15]#[N:23].[Cl:1][C:2]1[C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13][C:14]1[C:15]([NH2:23])=[C:16]([NH2:22])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1.[Cl:36][C:31]1[C:29]([NH2:30])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=[C:26]([O:25][CH3:24])[CH:32]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: COc1cc(Cl)c2[nH]nnc2c1
Agent: COc1cc(N)c(N)c(Cl)c1
Product: COc1cc(Cl)c(N)c([N+](=O)[O-])c1
Product: COc1cc(Cl)c2nn(CC(C)(N)C#N)nc2c1
Yield: 14 %

Procedure:
2-amino-3-(4-chloro-6-methoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile was prepared using a procedure similar to that described in Example 1, part a and b, except starting from 7-chloro-5-methoxy-1H-benzotriazole. 7-Chloro-5-methoxy-1H-benzotriazole (0.8 g) was prepared using a procedure similar to that described in Example 13, part a, except starting from 3-chloro-1,2-diamino-5-methoxybenzene. 3-Chloro-1,2-diamino-5-methoxybenzene (1.88 g, 75%) was prepared using a procedure similar to that described in Example 38, part a and b, except starting from 4-methoxy-2-nitroaniline (16.8 g) and N-chlorosuccinimide (15 g) in part a to yield 6-chloro-4-methoxy-2-nitroaniline (2.9 g, 14%) used in part b.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[CH:20]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:30](I)[C:24]=2[CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[CH:20]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:30]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=3[O:16][CH2:17][CH2:18][CH3:19])[C:24]=2[CH:23]=1)=[O:21]
Reactant: O=Cc1cc2c(I)cccc2s1
Reactant: CCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOc1c(-c2cccc3sc(C=O)cc23)cc(C(C)C)cc1C(C)C

Procedure:
A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-n-propoxy phenylboronic acid, 1.62 mmol of 2-formyl-4-iodo-benzo[b]thiophene and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-formyl-4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[Br:11][C:12]1[CH:13]=[C:14](I)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[Br:11][C:12]1[CH:17]=[C:16]([C:6]2[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Brc1cccc(I)c1
Reactant: O=Cc1ccc(B(O)O)o1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2cccc(Br)c2)o1
Yield: 25.9 %

Procedure:
5-Formyl-2-furanboronic acid (676 mg, 4.8 mmol) and 3-bromoiodobenzene (1132 mg, 4 mmol) were dissolved in 1,2-dimethoxyethane (30 mL), tetrakis(triphenylphosphine)palladium (228 mg, 0.2 mmol) was added thereto, 2 mol/L sodium carbonate (9.6 mL) was further added thereto, and the mixture was heated to reflux for 2 hours while stirring. After the reaction was completed water (20 mL) was added thereto, and extraction with ethyl acetate (20 mL×2) was carried out. The organic layer was washed with saturated brine, water was removed using anhydrous sodium sulfate, the solvent was then removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give 5-(3-bromophenyl)furan-2-carbaldehyde in a yield of 306 mg (yield 25.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])=[CH:6][CH:5]=1)([O-])=O.[CH2:17]([OH:19])[CH3:18]>[Pd]>[F:15][C:11]([F:16])([O:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:17](=[O:19])[CH3:18])=[CH:5][CH:6]=1)[CH:12]([F:14])[F:13]
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)cc1
Reactant: CCO
Agent: [Pd]
Product: CC(=O)Nc1ccc(OC(F)(F)C(F)F)cc1
Yield: 97 %

Procedure:
55 g of 1-nitro-4-(1,1,2,2-tetrafluoroethoxy)-benzene are hydrogenated in 300 ml of ethanol over 0.5 g of 10% strength palladium-on-charcoal in a circulatory hydrogenation apparatus under atmospheric pressure at 20°-45° C. for 1 hour, the catalyst is filtered off and the solution is concentrated in vacuo at 40° C. The 4-(1,1,2,2-tetrafluoroethoxy)aniline is diluted with 100 ml of glacial acetic acid, 23 ml of acetic anhydride are added dropwise at room temperature, 2 ml of water are added after 30 minutes, the solution is concentrated at 50° C. in vacuo after a short time and 500 ml of icewater are added. 56 g (97% of theoretical) of N-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-acetamide of m.p. 121°-122° C. are obtained.
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.O[C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]2=[O:43])=[CH:15][CH:14]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[N:1]1[C:2]([CH2:10][O:11][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: OCc1cn2ccccc2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCc3cn4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 83.8 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 920 mg of imidazo[1,2-a]-pyridin-2-ylmethanol (prepared as described in Preparation 20), 2.9 g of 5-(4-hydroxybenzyl)-3-tri-phenylmethylthiazolidine-2,4-dione, 1.4 g of tributyl-phosphine, 1.65 g of 1,1'-(azodicarbonyl)dipiperidine and 60 ml of benzene were used, to give 3.1 g of the title compound having Rf=0.71 (on silica gel thin layer chromatography using a 10:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[CH:40]=[N:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH2:43][C:44]([C:46]1[S:54][CH:53]2[CH:48]([CH2:49][N:50]([CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[Cl:62])[CH2:51][CH2:52]2)[CH:47]=1)=[O:45]>>[CH2:27]([O:34][C:35]1[CH:40]=[N:39][N:38]([CH2:43][C:44]([C:46]2[S:54][C:53]3[CH2:52][CH2:51][N:50]([CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[Cl:62])[CH2:49][C:48]=3[CH:47]=2)=[O:45])[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCl)C1=CC2CN(Cc3ccccc3Cl)CCC2S1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1cc2c(s1)CCN(Cc1ccccc1Cl)C2

Procedure:
5-Benzyloxy-2-{2-[5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2-yl]-2-oxo-ethyl}-2H-pyridazin-3-one is prepared following preparation 15b (in DMSO as solvent; purification via reversed HPLC chromatography) from 500 mg (2.47 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) and 1.03 g (2.72 mmol) 2-chloro-1-[5-(2-chloro-benzyl)-3a,4,5,6,7,7a-hexahydro-thieno[3,2-c]pyridin-2-yl]-ethanone (preparation 24).
Reaction SMILES: Cl.Cl.[C@H]1(CN2CCC(N[C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])CC2)[C@@H]2N(CCCC2)CCC1.CCN(C(C)C)C(C)C.[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([NH2:65])[CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:54])[CH3:53].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([NH:65][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[C:29]([O:32][CH2:33][C:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[O:36][CH:35]=2)[CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3c(OCc4coc5ccccc45)cccc3[nH]2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 307.5 %

Procedure:
To a ice-cold solution of 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (105, see example 50) (200 mg, 0.651 mmol) in 2 ml of dimethylformamide is added Huenigs base (334 ul, 1.95 mmol). After stirring at 0° C. for 10 min, 4-amino-piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.651 mmol) and PyBOP (356 mg, 0.684 mmol) are added subsequently. The mixture is stirred at room temperature over night. It is then diluted with ethyl acetate, washed with 1N-NaOH and brine, dried over anhydrous sodium sulphate and evaporated to give 980 mg of a lightbrown oil. The crude material is purified by chromatography on silicagel using cyclohexane and ethylacetate (1:1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4]([Br:10])([CH3:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(F)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClCCCl
Product: CC1(Br)C=C(Cl)C(F)=CN1
Temperature: 75 °C
Yield: 69 %

Procedure:
4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example 66, was dissolved in 50 mL of 1,2-dichloroethane in a dry flask. The resultant solution was heated, with stirring, to 75° C. and 4.09 (23 mmol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mmol) of 2,2-azobisisobutyronirile (AIBN), a free radical initiator. After the reaction mixture was stirred at 75° C. for 24 hours, it was diluted with 450 mL of methylene chloride and washed with 3 X 400 mL of water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as an amber oil; 1H NMR (CDCl3) d 4.50 (s, 2H), 7.54 (d, 1H), 8.44 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>ClCCl.C(N(C(C)C)CC)(C)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of 4-bromo benzylbromide (1.0 g, 4.1 mmol) in dichloromethane (20 ml) and diisopropyletylamine (1 ml) was added tert-butyl 4-piperidinylcarbamate (1.0 g, 5.0 mmol). The solution was then stirred at room temperature over night. The solvent was evaporated and 25 ml of 50% TFA in dichloromethane was added to the resulting white solid. The mixture was then stirred at room temperature for 2 h and then evaporated to dryness. The resulting solid was dissolved in water and extracted with toluene. After removal of the toluene the water phase was made basic with 1M NaOH giving a pH of 13. The water phase was then extracted with dichloromethane 3 times and the combined extracts were dried and then evaporated to give the pure product as a slightly yellow oil (0.96 g, 3.6 mmol)
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][C:19]3[N:20]([N:22]=[CH:23][CH:24]=3)[CH:21]=2)=[CH:12][CH:11]=1>CN(C=O)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[CH:18][C:19]3[N:20]([N:22]=[CH:23][C:24]=3[I:1])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2cn3nccc3cn2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cn3ncc(I)c3cn2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
N-iodosuccinimide (13 mg, 0.06 mmol) was added in one portion to a stirred solution of 6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyrazine (11 mg, 0.05 mmol) in dry DMF (0.5 ml) at RT under N2. After 30 minutes, a further portion of N-iodosuccinimide (13 mg, 0.06 mmol) in DMF (0.2 mmol) was added. After a further 30 minutes at RT the mixture was heated to 50° C. for 90 minutes. After cooling to RT, the reaction was quenched with saturated aqueous sodium thiosulphate/saturated NaHCO3 (1:1, 1 ml). The mixture was stirred at RT for 1 hour then partitioned between CH2Cl2/H2O. The mixture was passed through a phase separating cartridge. The organic layer was evaporated to give the title compound (13 mg, solid). 1H NMR (400 MHz, CDCl3): 9.01 (1H, d), 8.69 (1H, d), 8.05 (1H, s), 8.00-7.90 (2H, m), 7.24-7.14 (2H, m).
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:17]2=[N:18][CH:19]=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=[C:16]2[CH:15]=[CH:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH2:31][C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][CH2:43][CH:44]2[C:56]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[C:50]3[C:45]2=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:41])[CH2:35]1)=[O:33]>CN(C=O)C>[CH:46]1[C:45]2[CH:44]([CH2:43][O:42][C:40]([N:36]3[CH2:37][CH2:38][CH2:39][C@@H:34]([C:32](=[O:33])[CH2:31][N:22]([C:23]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:29])[C:20]4[N:21]=[C:16]5[CH:15]=[CH:14][N:13]([S:3]([C:6]6[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=6)(=[O:5])=[O:4])[C:17]5=[N:18][CH:19]=4)[CH2:35]3)=[O:41])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50]=2[CH:49]=[CH:48][CH:47]=1
Reactant: O=C(CBr)[C@@H]1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)[C@@H]4CCCN(C(=O)OCC5c6ccccc6-c6ccccc65)C4)C(=O)OC(C)(C)C)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
NaH (60% dispersion in mineral oil, 0.041 g, 1.0 mmol) was added to anhydrous DMF (5 mL). The suspension was cooled to about 0° C. and a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.40 g, 1.0 mmol) in anhydrous DMF (5 mL) was added drop-wise. The reaction mixture was allowed to warm to ambient temperature and (R)-(9H-fluoren-9-yl)methyl 3-(2-bromoacetyl)piperidine-1-carboxylate (0.441 g, 1.03 mmol, Preparation #LL.1) was added. The reaction mixture was stirred for about 30 min before it was partitioned between EtOAc (30 mL) and brine (2×100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (12 g column) eluting with a gradient of 10-50% EtOAc in heptane to give (R)-(9H-fluoren-9-yl)methyl-3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)piperidine-1-carboxylate as a clear oil (0.21 g, 26%): LC/MS (Table 2, Method a) Rt=3.16 min; MS m/z: 736 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[NH:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>S(=O)(=O)(O)O>[CH3:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]=1[NH:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C(=O)Nc1ccc(C(F)(F)F)cc1C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C(=O)Nc1c(C)cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
14.4 g (142.3 mmol) of potassium nitrate are added in small portions to an ice-cooled solution of 32.6 g (118.6 mmol) of ethyl N-(2-methyl-4-trifluoromethylphenyl)oxamate in concentrated sulfuric acid. After stirring at 0° C. for 1.5 hours, the mixture is cautiously poured onto 900 g of ice. The white suspension is extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated under reduced pressure in a rotary evaporator. Crystallization from ethyl acetate/hexane affords 35.5 g of the title compound as white crystals.
Reaction SMILES: C(Cl)(=O)OCC.[C:7]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13])([OH:9])=O.C(N(CC)CC)C.Cl.[Cl:26][CH2:27][CH2:28][NH2:29]>C(Cl)(Cl)Cl>[OH:9][CH:7]1[C:10]2[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:13])[N:29]1[CH2:28][CH2:27][Cl:26]
Reactant: NCCCl
Reactant: O=Cc1ccccc1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(O)N1CCCl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 32.7 %

Procedure:
9.7 ml (0.101 mole) of ethyl chlorocarbonate were dropwise added to a solution of 15.2 g (0.101 mole) of 2-carboxybenzaldehyde in 500 ml of chloroform and 14.1 ml (0.101 mole) of triethylamine, cooled to 0° C. After 45 minutes, a solution of 11.7 g (0.101 mole) of 2-chloroethylamine hydrochloride in 200 ml of chloroform and 14.1 ml (0.101 mole) of triethylamine was dropwise added thereto. The obtained solution was kept at 0°-5° C. for 5 hours. After warming to room temperature, the mixture was washed with water, 5% sodium bicarbonate, again with water and finally dried over sodium sulfate. 19 g of a crude product were obtained, which was purified on silica gel column eluting with methylene chloride-acetone 10/1 (v/v). 7 g of the title product were obtained; mp=133°-134° C. (methylene chloride).