Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(#N)C>C(=O)([O-])[O-].[K+].[K+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([NH:23][C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([F:19])=[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])[CH:14]=1)=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: OB(O)c1cccnc1
Reactant: CCCCNC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1
Temperature: 120 °C
Yield: 61 %

Procedure:
To 1-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-butyl-urea (P-1637, 14.0 mg, 0.0000323 mol), 3-pyridylboronic acid (5.96 mg, 0.0000485 mol), and Tetrakis(triphenylphosphine)palladium(0) (0.820 mg, 7.09E-7 mol) were mixed in 1.00 M potassium carbonate in water (1.00 mL) and acetonitrile (2.00 mL, 0.0353 mol). The resulting mixture was heated at 120° C. in the microwave for 40 minutes. The reaction was extracted with ethyl acetate and water twice, and the combined organic layers were washed with 1M sodium bicarbonate followed by brine and the organic layer was dried over magnesium sulfate and filtered. The organic layer was concentrated and purified by reverse phase HPLC (acetonitrile and water with 0.1% formic acid) to give the compound as a white solid (P-1637, 8.5 mg, 61%). MS(ESI) [M+H+]+=432.3.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:46](OC1C(C(O)=O)=NC(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)=NC=1O)[C:47]1[CH:52]=CC=CC=1.[Si](OCCNCC1CC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:45][CH:52]1[CH2:47][CH2:46]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Product: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
This compound was prepared by following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from ‘5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (225 mg, 0.50 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amine (8i) (170 mg, 0.74 mmol). The yield was 307 mg, 93% of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36]([OH:38])=O)[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][NH:54]C(C2(C3C=CC=CC=3)CCNCC2)=O)[CH2:48][CH2:47]1>CO.ClCCl>[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][NH:54][C:36]([C:33]2([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C:9]3([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]4[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=4)[CH2:10]3)[CH2:35][CH2:34]2)=[O:38])[CH2:48][CH2:47]1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(NCCN1CCOCC1)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)NCCN4CCOCC4)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 26FH.5 using 1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid (0.16 g, 0.625 mmol) and 4-phenyl-piperidine-4-carboxylic acid (2-morpholino-ethyl)-amide hydrochloride (0.07 mL, 0.5 mmol). Chromatograph on silica gel eluting with 6% methanol/dichloromethane to give the title compound: Rf =0.34 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([F:22])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(OC)(C)C>[C:13]([O:12][C:11]([N:10]1[CH2:18][CH2:19][O:21][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:22])[CH2:9]1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Br)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, tert-butyl 2-(4-bromo-2-fluoro-phenyl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (7.385 g, 19.5 mmol, Eq: 1.00) and triphenylphosphine (6.15 g, 23.4 mmol, Eq: 1.2) were dissolved in TBME (33 ml). Under ice-bath cooling, DIAD (5.04 g, 4.85 ml, 23.4 mmol, Eq: 1.2) was added (exotherm). The yellow solution was stirred at RT overnight. The RM became a yellow suspension. Control with TLC: the reaction was finished. The solvent was evaporated. TBME was added and the solid was filtered. The filtrate was evaporated. The crude material was purified by flash chromatography (silica gel, 100 g, 5% to 40% EtOAc in heptane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[CH2:31]2.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([CH:38]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[CH2:31]3)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 34.8 %

Procedure:
A mixture of 3,4-dichlorophenyl-acetic acid (0.31 g, 1.5 mmol) and CDI (0.26 g, 1.6 mmol) in DMF (20 mL) was stirred at 70° C. under N2. After 4 h, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.47 g, 1.5 mmol) was added. The mixture was cooled to 40° C. and was stirred at this temperature for an additional 16 h. Water (30 mL) was added resulting in precipitation of the product. The solid precipitate was filtered, washed with water (50 mL) and dried in vacuo providing 2-(3,4-dichloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-acetamide as a yellow solid (0.24 g, 34% yield); mp 191-193° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4. 4.17 (98.19%); 1H NMR (DMSO-d6) δ 1.98-2.02 (m, 1H), 2.32-2.45 (m, 1H), 2.57-2.73 (m, 1H), 2.86-2.98 (m, 1H), 3.54 (s, 2H), 4.45-5.14 (m, 4H), 5.11 (dd, 1H, J=13.2, J=5.1), 7.24 (dd, 1H, J=8.4, J=6.3), 7.29-7.47 (m, 2H), 7.48-7.59 (m, 2H), 7.67 (d, 1H, J=7.8), 8.72 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 41.0, 42.3, 47.1, 51.6, 122.1, 123.0, 127.1, 129.1, 129.5, 130.3, 130.4, 130.6, 131.1, 137.3, 142.3, 143.6, 168.0, 169.4, 170.9, 172.8; LCMS: MH=461, 463; Anal. Calcd for C22H19Cl2N3O4+0.5H2O: C, 56.30; H, 4.30; N, 8.95. Found: C, 56.19; H, 3.91; N, 8.56.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: C1CNCCN1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(N2CCNCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 17 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using piperazine instead of thiomorpholine to the title compound (SiO2, dichloromethane:(dichloromethane: methanol:ammonia=70:27:3)=92:2 to 50:50, 40 mg, 17%) which was obtained as an off-white solid. MS: m/e=418.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][NH:17][NH2:18]>CO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:17]([CH3:16])[NH2:18])[CH:7]=1
Reactant: CNN
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(N)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 112.7 %

Procedure:
2 g of 4,6-dichloropyrimidine were dissolved in 30 ml of methanol, mixed with 1.37 g of triethylamine and 0.63 g of methyl hydrazine and stirred for 2 days at room temperature. 0.1 ml of methyl hydrazine and 0.2 ml of triethylamine were then added and stirred for 4 days at room temperature. After rotating out the solvent, a residue of 2.4 g of crude 6-chloro-4-(1-methyl-hydrazino)-pyrimidine were obtained, which was immediately processed further.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].[NH4+:14].[OH-]>S(Cl)(Cl)=O>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH2:14])=[O:6]
Reactant: Cc1nccc(C(=O)O)c1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: Cc1nccc(C(N)=O)c1[N+](=O)[O-]

Procedure:
A mixture of 0.5 g 2-methyl-3-nitroisonicotinic acid and 20 ml of thionyl chloride was refluxed gently for 30 min. and the excess thionyl chloride was removed in vacuo to leave an oil, which was treated with conc. NH4OH under cooling for 20 min. and extracted with EtOAc. The extract was washed with water and dried, the solvent was removed to give an oil, which was purified over silica gel to yield 0.2 g of 2-methyl-3-nitroisonicotinamide, mp 203° - 204° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[CH2:18][CH2:19][NH:20][CH2:21][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>O1CCOCC1>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[CH2:18][CH2:19][N:20]([C:30](=[O:31])[NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=3)[CH2:21][C:10]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)Cn1c2c(c3ccccc31)CCNC2
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)N2CCc3c(n(CC(=O)OC(C)(C)C)c4ccccc34)C2)c1

Procedure:
A solution of 9-tert-butyloxycarbonylmethyl-1,2,3,4-tetrahydro-9H-pyrido [3,4-b]indole (3.56 g, 12.0 mmol) and 3-methylphenylisocyanate (1.60 ml, 12.4 mmol) was stirred in dioxan (40 ml) at room temperature for 4 hours. Evaporation of the solvent and chromatography on silica gel with ethyl acetate-hexane (1:3) as eluant gave the product. (3.29 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]#[CH:13])=[CH:7][CH:6]=2.[N:14]([Si](C)(C)C)=[N+:15]=[N-:16]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:16][NH:15][N:14]=1)=[CH:7][CH:6]=2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2cnc(Cl)cc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cc2cc(-c3cn[nH]n3)ccc2cn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
3-chloro-6-ethynylisoquinoline (Preparation 50, 120 mg, 0.64 mmol) was dissolved in dry DMF (1 mL). Azidotrimethylsilane (1 mL, 7.5 mmol) was added and the reaction stirred at 120° C. for 2 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 2% 7N NH3 in methanol in DCM followed by elution through an SCX-2 column using 50% methanol in chloroform followed by 50% 7N NH3 in methanol in chloroform to afford the title compound as a pale brown powder (90 mg, 61%).
Reaction SMILES: [NH2:1][CH:2](/[CH:9]=[C:10](/[CH2:19][P:20]([OH:23])([OH:22])=[O:21])\[CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH2:3][C:4]([O:6]CC)=[O:5]>O>[NH2:1][CH:2](/[CH:9]=[C:10](/[CH2:19][P:20]([OH:23])([OH:22])=[O:21])\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CCC/C(=C\C(N)CC(=O)OCC)CP(=O)(O)O
Solvent: O
Product: NC(/C=C(\CCCC(=O)O)CP(=O)(O)O)CC(=O)O

Procedure:
1.3 g (4:0 mmol) of diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate are heated in 15 ml of water for 23 hours to reflux. The reaction mixture is concentrated to 7 ml and the residue is stirred in an ice bath. The precipitated product is isolated by filtration, affording E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylic acid of m.p. 192° C. (dec.).
Reaction SMILES: [C:1]([C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)(=O)[CH3:2]>O1CCOCC1.Cl>[CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)[CH3:2]
Reactant: CC(=O)c1c(O)ccc2c1CCCC2
Agent: Cl
Solvent: C1COCCO1
Product: CCc1c(O)ccc2c1CCCC2

Procedure:
5-Acetyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene (15.0 g) was heated at reflux in a mixture of dioxan (40 ml) and 50% HCl (50 ml) containing zinc amalgam (16.0 g) for 18 hours. The mixture was cooled, filtered and the filtrate was extracted with ether. The ether extracts were washed with water, dried (MgSO4), filtered and evaporated to dryness leaving a solid which crystallised from petroleum ether (60°-80°) to give 5-ethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene as pale yellow needles, 13.5 g (97%), mp 94°-5°.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[H][H].N.Cl>[Ni].C(O)C>[NH2:2][CH2:1][C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)Nc2ccc(C(C)(C)C#N)cc2)cc1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc(C(C)(C)CN)cc2)cc1

Procedure:
5 g. N-[4-(1-Cyano-1-methylethyl)-phenyl]-4-methoxybenzamide (Example 27) are hydrogenated at 90° C. and 120 bar hydrogen pressure in 40 ml. ethanol in the presence of 40 ml. liquid ammonia and 2 g. Raney nickel. The reaction mixture is filtered and the filtrate evaporated to dryness in a vacuum. After column chromatographic purification (400 ml. silica gel 60; dichloromethane/methanolic ammonia 30:1 v/v), there are obtained 2.6 g. of colourless crystals which are heated in 100 ml. 1M hydrochloric acid. After cooling, there are obtained 2.3 g. (40% of theory) of the title compound as hydrochloride in the form of colourless leaflets; m.p. 273°-276° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[N:25]=[C:26]([CH3:35])[N:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:28]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:44])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[N:25]=[C:26]([CH3:35])[N:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:28]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:10][CH2:11]2)[CH2:6]1)#[N:2]
Reactant: Cc1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)cn3COCC[Si](C)(C)C)cn1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CC(C#N)C4)C4CC4)c3n2)cn1-c1ccccc1
Yield: 61.9 %

Procedure:
2-(2-Methyl-1-phenyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (68 mg, 0.111 mmol) was dissolved in 0.6 mL of dichloromethane and then stirred in an ice bath. Trifluoroacetic acid (0.4 mL) was added slowly and the ice bath was removed. The reaction was stirred for 3 h and then cooled in ice bath. Sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in 4 mL of absolute ethanol, sodium acetate (183 mg) was added and the mixture was stirred for 20 h at 60° C. The reaction was cooled, and water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 33 mg (62%) of 2-(2-methyl-1-phenyl-1H-imidazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. MS: (M+H)+=481; mp=175-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]12[S:22][CH:18]([CH2:19][CH2:20][CH2:21]1)[CH2:17][CH:16]([CH:23]=[O:24])[CH2:15]2>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:23]([CH:16]2[CH2:17][CH:18]3[S:22][CH:14]([CH2:21][CH2:20][CH2:19]3)[CH2:15]2)[OH:24])=[CH:4][CH:3]=1
Reactant: O=CC1CC2CCCC(C1)S2
Reactant: Brc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)C1CC2CCCC(C1)S2
Temperature: -25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of 1-bromo-4-iodobenzene (1.462 g, 5.17 mmol) in THF (13 ml) at −30° C. to −25° C. was added isopropylmagnesium chloride 2M in THF (2.82 ml, 5.64 mmol). The reaction mixture was stirred at −30 to −20° C. for 2 hrs, allowed to warm to −3° C. and 9-thia-bicyclo[3.3.1]nonane-3-carbaldehyde (800 mg, 4.70 mmol) was added, the syringe was rinsed with THF (1 ml) and the solution was stirred for 1.5 hrs while cooled in an ice bath. The reaction mixture was quenched at 0° C. with a solution of aqueous saturated NH4Cl and water 2/1 (15 ml), diluted with ethyl acetate and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried using Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluting with a gradient of hexanes:MTBE 98:02 to 70:30) yielding the title intermediate (1.11 g, 2.88 mmol, 61%) as a colourless resin.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:13])([CH3:12])[CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.Br[C:15]#[N:16]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:12])[CH2:9][N:10]([CH3:11])[C:15](=[NH:16])[NH:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNCC(C)(N)c1cccc(Br)c1
Reactant: N#CBr
Solvent: CCO
Product: CN1CC(C)(c2cccc(Br)c2)NC1=N
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.4 %

Procedure:
To a solution of 2-(3-bromophenyl)-N1-methylpropan-1,2-diamine (0.12 g, 0.50 mmol) in EtOH (10 mL) was added BrCN (0.073 g, 0.70 mmol, 1.4 eq). The mixture was stirred at RT for 16 h and then concentrated in vacuo. The residue was redissolved in CHCl3 (20 mL) and the solution was washed with 15% NaOH (10 mL). The aqueous layer was extracted with CHCl3 (3×10 mL) and the combined organic layer was dried (MgSO4), and concentrated to give 0.14 g (100%) of 4-(3-bromophenyl)-1,4-dimethylimidazolidin-2-imine (CD4; R1=Me, R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 7.42 (t, J=1.7 Hz, 1H), 7.35 (dd, J=8.1, 1.7 Hz, 2H), 7.15 (t, J=8.1 Hz, 1H), 3.62 (d, J=9.3 Hz, 1H), 3.53 (d, J=9.0 Hz, 1H), 3.08 (s, 3H), 1.56 (bs, 3H). MS (ESI) m/e 268.1, 270.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH3:21])[CH:18]=1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To 2,3,5-trichloropyridine (25 g) were added 1-BOC-piperazine (28.13 g), potassium carbonate (37.86 g), N,N-dimethylformamide (25 mL) and toluene (50 mL), and the mixture was stirred at 100° C. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (39.13 g). To 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.35 g) were added palladium (II) acetate (0.46 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.71 g), potassium fluoride (9.556 g), methylboronic acid (5 g) and tetrahydrofuran (202 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g). To 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g) were added 4N hydrogen chloride/ethyl acetate (18.2 mL) and chloroform (45.5 mL), and the mixture was stirred at room temperature. After completion of the reaction, to the reaction mixture were added water and potassium carbonate, and the mixture was extracted with ethyl acetate. The solvent was evaporated to give the title compound (3.3 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[C:3]([CH3:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Reactant: Nc1nccc(C(=O)O)n1
Agent: Cl
Product: Cc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Yield: 36 %

Procedure:
The title compound is prepared in 36% yield (95 mg, clear pale yellow oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.74 mmol, Amine-17, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (103 mg, 0.74 mmol) by the similar manner in Step-1 of Example 8.