Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.CC1C=CC(S(O[CH2:32][CH2:33][C@@H:34]2[CH2:36][C@@H:35]2[CH:37]2[CH2:42][CH2:41][N:40]([C:43]3[N:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=3)[CH2:39][CH2:38]2)(=O)=O)=CC=1.[I-].[K+]>C(#N)C.O>[Cl:49][C:46]1[CH:45]=[N:44][C:43]([N:40]2[CH2:41][CH2:42][CH:37]([C@H:35]3[CH2:36][C@H:34]3[CH2:33][CH2:32][NH:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[N:9]=[C:10]4[CH3:18])[CH2:38][CH2:39]2)=[N:48][CH:47]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(N)ccc32)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(Cn2nc(C)c3cc(NCC[C@@H]4C[C@@H]4C4CCN(c5ncc(Cl)cn5)CC4)ccc32)cc1
Temperature: 110 °C
Reaction time: 1.33 h

Procedure:
1-(4-methoxybenzyl)-3-methyl-1H-indazol-5-amine (51 mg, 0.34 mmol) from step 2 of this example, 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from step 1 of Example 5 (75 mg, 0.17 mmol) and potassium iodide (3 mg, 0.017 mmol) combined and the solids slurried in acetonitrile. The slurry was reacted in the microwave with stirring for 80 minutes at 110° C. using normal power. The mixture was cooled to RT, diluted with 4:1 water:saturated sodium bicarbonate (40 ml), extracted with EtOAc (3×40 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 10% acetone:DCM to give the titled compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24].[Cl-].[NH4+]>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([OH:25])([CH3:24])[CH2:14][C:13]#[N:15]
Reactant: CC#N
Reactant: CC(=O)c1ccccc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)(CC#N)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
To a stirring solution of diisopropylamine (0.97 mL, 6.83 mmol) in tetrahydrofuran (15 mL) at −78° C. under nitrogen was added a solution of n-butyllithium (2.86 mL, 7.14 mmol, 2.5 M in hexane). After the addition was complete, the mixture was stirred at −78° C. for 10 minutes and removed cooling bath for 5 minutes. The mixture was cooled back to −78° C., acetonitrile (0.33 mL, 6.21 mmol) was added and the reaction mixture was then stirred at −78° C. for 30 minutes. 1-(2-Chloro-phenyl)-ethanone (1 mL, 7.45 mmol) was added and the resulting solution was allowed to warm to ambient temperature. After 18 hours at ambient temperature, saturated aqueous ammonium chloride (5 mL) was added to the reaction mixture and it was concentrated at reduced pressure. The resulting crude product was diluted with ethyl acetate (30 mL), washed with water (15 mL) followed by saturated aqueous sodium chloride (10 mL). The organic layer was concentrated and purified by column chromatography (40 g silica gel cartridge) eluting with ethyl acetate/hexane (0%-15%) to give the product as a colorless oil (1.1 g, 90%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:33]=[CH:32][C:20]([CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH2:25]3)=[CH:19][CH:18]=1>C1COCC1>[O:31]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][CH:30]=[C:22]([CH2:21][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])=[CH:33][CH:32]=3)[CH:23]=2)[NH:27]1
Reactant: Nc1ccc(Cc2ccc3c(c2)CC(=O)N3)cc1
Reactant: CCn1nc(C)cc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)CC(=O)N3)cc1
Temperature: 79 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.168 g, 1.09 mmol) and thionyl chloride (4 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by distillation. The crude acid chloride was cooled to 65° C., and then dissolved in THF (5 mL). 5-(4-Amino-benzyl)-1,3-dihydro-indol-2-one (0.200 g, 0.840 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. Subsequently, the reaction mixture was allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a pale yellow precipitate. The pale yellow solids were filtered to afford the pure product (0.141 g, 0.377 mmol, 34.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17](=O)[C:18]([CH3:24])([CH3:23])[C:19](OC)=[O:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH3:24])([CH3:23])[C:19](=[O:20])[NH:27][N:28]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OCc2ccccc2)c1
Reactant: NN
Solvent: O
Product: COc1ccc(C2=NNC(=O)C2(C)C)cc1OCc1ccccc1

Procedure:
Prepared analogously as described for example C1 using methyl 3-[3-(benzyloxy)-4-methoxyphenyl]-2,2-dimethyl-3-oxopropanoate (compound D4) and hydrazine hydrate as starting compounds.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH2:39][CH:40]([OH:42])[CH3:41]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH2:39][CH:40]([OH:42])[CH3:41])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(O)CCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: CC(O)CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-amino-2-butanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (d, J=6.32 Hz, 3 H), 1.37-1.87 (m, 10 H), 2.36-2.45 (m, 2 H), 3.32-3.48 (m, 5 H), 3.63-3.77 (m, 2 H), 4.12-4.23 (m, 4 H), 4.62 (br. s., 1 H), 7.14 (ddd, J=9.05, 6.63, 2.21 Hz, 2 H), 7.37-7.44 (m, 2 H), 7.99 (d, J=1.05 Hz, 1 H), 8.56 (d, J=1.26 Hz, 1 H), 10.35 (t, J=5.69 Hz, 1 H), 17.26 (s, 1 H); ES+ MS: 539 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15]>>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:13][C:14](=[O:15])[NH:1]2
Reactant: Nc1cc(Cl)cc(Cl)c1C(=O)O
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2c(Cl)cc(Cl)cc2[nH]1
Temperature: 160 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A mixture of 2 g (10 mmol) of 2-amino-4,6-dichlorobenzoic acid and 1.6 g (30 mmol) of urea was heated to 160° C. for 2 hrs. and at 180° C. for a further 2 hrs. The resulting brown mass was triturated with 200 ml of methanol, filtered off and dried in a vacuum. 880 mg (40%) of 5,7-dichloro-1,2,3,4-tetrahydroquinazoline-2,4-dione were obtained as beige crystals;
Reaction SMILES: Cl.CN(CCCN=C=NCC)C.[NH2:13][CH2:14][C:15]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]2[C:16]=1[N:17]=[C:18]([O:30][CH3:31])[C:19]([O:28][CH3:29])=[N:20]2.[CH3:32][O:33][P:34]([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])([O:36][CH3:37])=[O:35]>C(Cl)Cl>[CH3:29][O:28][C:19]1[C:18]([O:30][CH3:31])=[N:17][C:16]2[C:21](=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:15]=2[CH2:14][NH:13][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][P:34]([O:33][CH3:32])([O:36][CH3:37])=[O:35])[N:20]=1
Reactant: COP(=O)(CCCC(=O)O)OC
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1nc2cc([N+](=O)[O-])cc(CNC(=O)CCCP(=O)(OC)OC)c2nc1OC
Reaction time: 30 h

Procedure:
163 mg (0.851 mmol) of N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride are added at room temperature to a solution of 150 mg (0.568 mmol) of 5-aminomethyl-2,3-dimethoxy-7-nitroquinoxaline and 165 mg (0.738 mmol) of 4-(dimethylphosphono)butyric acid in 3 ml of methylene chloride and the mixture is stirred for 30 hours. The mixture is then diluted with methylene chloride and washed with 0.2N hydrochloric acid and brine and concentrated on a rotary evaporator, and the residue is dried in a high vacuum. The title compound is obtained as a yellow resin.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[CH:7]=[C:8]([CH3:16])[CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=[O:5].[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:24][NH:25]2)=[CH:21][CH:20]=1.CC(C)([O-])C.[K+].C1COCC1.Cl>CN(C=O)C>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][C:8]([CH3:16])=[CH:7][C:6]=2[C:4](=[O:5])[C:3]([NH:31][C:29](=[O:30])[CH2:28][C:23]2[C:22]3[C:26](=[CH:27][C:19]([F:18])=[CH:20][CH:21]=3)[NH:25][CH:24]=2)=[O:17])[CH:11]=[CH:12]1
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Reactant: COC(=O)C(=O)c1cc(C)cc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C(=O)NC(=O)Cc2c[nH]c3cc(F)ccc23)c2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 21.7 %

Procedure:
To a mixture of (1,5-dimethyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.51 g, 2.21 mmol) and 2-(6-fluoro-1H-indol-3-yl)-acetamide (0.38 g, 2 mmol) in DMF (20 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 8.0 mL, 8.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 11 h, treated with concentrated hydrochloric acid (2 mL) and then heated at 50° C. for 2 h. The mixture was cooled to room temperature, extracted with ethyl acetate and the extract was washed with water, saturated aqueous sodium bicarbonate and brine dried (sodium sulfate), filtered and evaporated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 2-(1,5-dimethyl-1H-indol-7-yl)-N-[2-(6-fluoro-1H-indol-3-yl)-acetyl]-2-oxo-acetamide (170 mg, 23%) and 3-(1,5-dimethyl-1H-indol-7-yl)-4-(6-fluoro-1H-indol-3-yl)-pyyrole-2,5-dione (340 mg, 45.5%). 1H NMR (d6-DMSO, 400 MHz) δ 2.26 (s, 3H), 3.58 (s, 3H), 6.36 (d, J=3.13 Hz, 1H), 6.40˜6.45 (m, 2H), 6.73 (s, 1H), 7.11 (dd, J1=2.34 Hz, J2=9.38 Hz, 1H), 7.16 (d, J=3.13 Hz, 1H), 7.7.39 (s, 1H), 7.80 (d, J=3.13 Hz, 1H), 11.14 (s, 1H), 11.82 (s, 1H); MS (ES, m/z): C22H16FN3O2: 374.2 (M++1); 372.2 (M+−1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15](=[NH:17])[NH2:16])=[N:7]1.C[O:23][CH:24]=[C:25]([C:30](OC)=O)[C:26]([O:28][CH3:29])=[O:27].C[O-].[Na+]>CO>[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]2[N:16]=[C:24]([OH:23])[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][N:17]=2)=[N:7]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: COC=C(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O

Procedure:
10.0 g (32.7 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride (example 5A) and 8.54 g (49.1 mmol) of dimethyl (methoxymethylene)malonate were initially charged in 400 ml of methanol, and 1.77 g (32.7 mmol) of sodium methoxide were added cautiously. The mixture was reacted at 50° C. overnight. The precipitate formed was filtered off, washed with a little methanol and dried under high vacuum. Thus, 6.54 g (52% of theory) of the target compound were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][CH3:35])[CH2:28][CH2:27]2)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][N:34]([CH3:35])[C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:30][CH2:31]2)=[CH:11][CH:10]=1
Reactant: CNCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Clc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ncccn1
Yield: 76.5 %

Procedure:
A mixture of 1.8 parts of 2-chloropyrimidine, 6 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-N-methyl-1-piperidineethanamine, 1.7 parts of sodium hydrogen carbonate and 120 parts of ethanol was stirred and refluxed overnight. The reaction mixture was evaporated. Water was added. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 1,1'-oxybisethane (50:50 by volume). The product was filtered off and dried, yielding 5.5 parts (76.5%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-N-methyl-2-pyrimidinamine; mp. 135.4° C. (514).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH2:25])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15].[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH:25][C:29]([C:28]1[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:27]=1[Br:26])=[O:30])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: O=C(Cl)c1c(Cl)cccc1Br
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(Cl)cccc2Br)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (250 mg, 0.69 mmol) in tetrahydrofuran (2 ml) was added 2-bromo-6-chlorobenzoyl chloride (192.7 mg, 0.76 mmol) followed by diisopropylethylamine (178 mg, 1.38 mmol). The reaction was left stirring under nitrogen overnight. LC-MS analysis showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was redissolved in dichloromethane and washed with 2M hydrochloric acid followed by water. The organic layer was concentrated in vacuo to give the title compound (280 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:13]Br.ClCCl.O>C(Cl)(Cl)Cl>[Br:13][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: BrBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Oc1ccc(OC(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 4-trifluoromethoxyphenol (35.6 g, 0.2 mol) in chloroform (280 ml) was added dropwise a solution of bromine (32 g, 0.2 mol) in chloroform (50 ml). The solution was stirred at 0° C. for 1 hour and at room temperature for 2 hours. Dichloromethane (200 ml) and water (400 ml) ware added and the organic phase was washed further with water(400 ml), brine (200 ml) and dried (MgSO4). The solvent was removed and the residue was purified by distillation at reduced pressure to give the title compound. 1H NMR (250 MHz, CDCl3) δ 7.38 (1H, d, J=2.1 Hz), 7.13 (1H, dd, J=9.1, 2.1 Hz), 7.03 (1H, d, J=9.1 Hz), and 5.53 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:9](I)[CH3:10]>N>[CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)([CH2:9][CH3:10])[CH3:2]
Reactant: CCc1ccncc1
Reactant: CCI
Agent: N
Product: CCC(C)c1ccncc1

Procedure:
A method similar to that of Brown and Murphey is employed.4Approximately 500 ml of NH3 was condensed in a 1-liter flask; 1 mole of sodium amine (Fisher) followed by 1.0 mole of 4-ethylpyridine is added to the flask. After stirring under NH3 reflux for 30 minutes, 1.1 mole of ethyl iodide is added via an addition funnel to the orange-red suspension over a 1.5 hour period. Stirring is continued after the ethyliodide addition is complete and the solvent is allowed to evaporate slowly. Water (50 ml) is added to the residue and the layers are separated. The aqueous layer is extracted with ether and the combined organic layers are dried over Na2CO3, concentrated, and distilled. A colorless oil, 117.2 gm (87%), bp 120-25/90mm (lit.5 128°-30°/100 mm) is collected. The oil exhibits an nmr signal typical for a sec-butyl group in addition to the usual pattern for 4-substituted pyridine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][OH:9].[Br:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[CH:17]=1.O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:21]=1
Reactant: COc1ccc(CO)cc1OC
Reactant: Fc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(F)cc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
Sodium hydride (80% disp. in oil; 933 mg, 31.1 mmol) was added, all at once, to 3,4-dimethoxybenzyl alcohol (3.48 g, 20.7 mmol) in DMF (40 mL) at 0° C. and under Ar. After 5 min., the mixture was allowed to warm to r.t. After 1 h, 1-bromo-3,5-difluorobenzene (4 g, 20.7 mmol) in DMF (5 mL) was added dropwise at r.t. The resulting mixture was kept at this temperature for 16 h and slowly poured into H2O (500 mL). It was extracted with EtOAc (3×) and the combined organics were washed with 25% NH4OAc buffer (1×), H2O (2×) and brine. The solution was dried (MgSO4) and concentrated to give a pale yellow solid that was purified by column chromatography on silica gel (EtOAc:hexane, 10:90-15:85) to afford the title compound as a white solid (5.85 g, 83%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][C@H:16]([NH:18][CH3:19])[C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[C:32]1([O:31][C:29](=[O:30])[N:18]([C@@H:16]2[C@@H:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Product: CN(C(=O)Oc1ccccc1)[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid phenyl ester was prepared from rac-(1-cyclopropylmethyl-piperidin-4-yl)-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using phenyl chloroformate instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 530.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[N:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:27]=[C:28]([CH2:32][NH2:33])[CH:29]=[CH:30][CH:31]=2)[CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:33][CH2:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([N:24]5[CH:25]=[N:21][N:22]=[CH:23]5)[CH:27]=4)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Reactant: NCc1cccc(-n2cnnc2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(NCc3cccc(-n4cnnc4)c3)c2C1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (80 mg, 0.26 mmol) and (3-(4H-1,2,4-triazol-4-yl)phenyl)methanamine (120 mg, 0.40 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (0.6 mL, 4 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-50% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[N:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)C(C3C=CC=CC=3)[N:10]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[C:9]2=[O:37])=[CH:4][CH:3]=1.Cl>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)([CH3:38])[C:9]([NH:10][C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=2)=[O:37])=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(Br)cc2)C(=O)N(c2ccc(C(F)(F)F)cc2)C(c2ccccc2)N1CCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Product: CC(NCCN1CCOCC1)(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 27.4 %

Procedure:
The 5-(4-bromo-phenyl)-5-methyl-1-(2-morpholin-4-yl-ethyl)-2-phenyl-3-(4-trifluoromethyl-phenyl)-imidazolidin-4-one (1.0 g, 1.7 mmol) was stirred vigorously in a solution of dichloromethane:conc. HCl (10 mL: 50 mL, v:v) overnight at 80 degrees Celcius. The resulting mixture was cooled to room temperature and the aqueous portion was extracted with dichloromethane. The aqueous portion was then basified to pH 11 with aqueous NaOH. The aqueous layer was then extracted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with dichloromethane:methanol gradient (500:1 to 100:1, v/v) to afford the product as a pale yellow solid (233 mg, 27%). MS: calc'd 500 (MH+), exp 500 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]#[C:17][Si](C)(C)C)=[CH:15][C:10]3=[N:9][C:8]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3([NH2:32])[CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C>C1COCC1>[C:16]([C:14]1[CH:13]=[CH:12][N:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4([NH2:32])[CH2:29][CH2:30][CH2:31]4)=[CH:24][CH:23]=3)[N:9]=[C:10]2[CH:15]=1)#[CH:17]
Reactant: C[Si](C)(C)C#Cc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#Cc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
To a solution of 1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (31 mg, 0.07 mmol) in THF (0.5 mL) was added a 1 M solution of tetra-n-butylammonium fluoride in THF (0.2 mL, 0.2 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for 18 h, then was separated between water (15 mL) and EtOAc (15 mL). The aqueous layer was extracted with EtOAc (2×15 mL). The combined organic phases were washed with water (15 mL), dried (Na2SO4 anh) and concentrated under reduced pressure. The remaining material was treated with triethylamine (0.03 mL, 0.21 mmol, 3.0 equiv) and the resulting material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 8.5 min., gradient to 95% CH2Cl2: 5% MeOH over 7 min.; 95% CH2Cl2: 5% MeOH for 9 min.) to give 1-[4-(7-ethynyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (12 mg, 39%).