Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:27]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O>N1CCCCC1.C(O)C>[O:16]=[C:12]1[C:11](=[CH:17][C:19]2[NH:20][C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=3[C:27]=2[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)[nH]c2c1CCCC2
Reaction time: 4 h
Yield: 33.3 %

Procedure:
A mixture of 90 mg 6-phenyl-2-oxindole, 95 mg 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid and piperidine ( 3 drops) in ethanol (2 mL) was held in a sealed tube at 90° C. for 4 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid. The precipitate was collected by filtration and washed with water and hexane to give 59 mg of 3-[2-(2-oxo-6-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3yl]-propionic acid as a brown solid (31% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:30])[NH:4][CH:5]=[C:6]([C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:18]=[CH:17]3)([OH:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.[H-].[Na+].I[CH3:34]>CN(C=O)C.O>[CH3:34][N:4]1[CH:5]=[C:6]([C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:18]=[CH:17]3)([OH:13])[C:9]([F:10])([F:11])[F:12])[CH:7]=[C:2]([CH3:1])[C:3]1=[O:30]
Reactant: Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn(C)c1=O
Reaction time: 1 h
Yield: 27.7 %

Procedure:
To a solution of 3-methyl-5-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyridin-2-one (0.184 mmol) in 1 mL DMF was added NaH (0.221 mmol; 60% suspension in oil) in several portions. After 1 hour, iodomethane (0.20 mmol) was added. After 1 hour, the mixture was diluted with water and the solid was collected by filtration, washed with water and dried. The residue was purified with flash silica gel chromatography using 25% hexanes in ethyl acetate. The product-rich fractions were concentrated in vacuo to provide the title compound (0.051 mmol), m.p.>200° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:11][CH2:12][CH2:13][OH:14])[CH:3]=[CH:2]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCCl>[CH2:26]([O:25][C:23](=[O:24])[N:11]([CH2:12][CH2:13][OH:14])[CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCCNCc1cccc2cc[nH]c12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N(CCO)Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
To a solution of 2-[(1H-indol-7-ylmethyl)-amino]-ethanol (4.4 g) in 1,2-dichloroethane (40 mL) was added triethylamine (4.85 mL, 34.6 mmol) followed by benzyl chloroformate (3.57 mL, 25.34 mmol). The mixture was allowed to stir at room temperature for 2 hours. The mixture was quenched by addition of water (20 mL), and 1.0 M sodium hydroxide (10 mL). The organic layer was separated and the aqueous layer extracted with 1,2-dichloroethane (20 mL). The combined organic extracts were washed with 1.0 M hydrochloric acid (20 mL), water (20 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate in hexanes to 40% ethyl acetate in hexanes to afford (2-hydroxy-ethyl)-(1H-indol-7-ylmethyl)-carbamic acid benzyl ester (2.79 g, 52% combined yield for two steps) as a colorless oil. 1H NMR (CDCl3) 400 MHz δ: 9.97 (br s, 1H), 7.75-6.9 (m, 8H), 6.54 (br s, 1H), 5.21 (s, 2H), 4.9-4.6 (m, 3H), 3.85-3.57 (m, 2H), 3.55-3.23 (m, 3H); LCMS M+H=325.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[CH3:19][O:20][C:21](=[O:46])[N:22]=[C:23]([S:44][CH3:45])[C:24](=[N:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=1)[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([OH:33])[C:26]=1[F:34].O>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:46])[N:22]=[C:23]([S:44][CH3:45])[C:24]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:26]=1[F:34])=[N:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(O)c1F
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCCO[Si](C)(C)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
After adding 0.489 g of cesium carbonate and 0.348 ml of (3-bromopropoxy)-t-butyldimethylsilane to a solution of 0.401 g of [2-(4-cyanophenylimino)-2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester in 10 ml of DMF, the mixture was stirred at room temperature for 24 hours. Next, 50 ml of water was added to the reaction mixture and extraction was performed with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 0.517 g of the title compound.
Reaction SMILES: [CH3:1][C@@:2]([C:9]([OH:11])=[O:10])([CH2:4][CH2:5][C:6](O)=[O:7])[NH2:3].C(B(CC)CC)C.B>C1COCC1>[NH2:3][C:2]([CH3:1])([CH2:4][CH2:5][CH2:6][OH:7])[C:9]([OH:11])=[O:10]
Reactant: C[C@](N)(CCC(=O)O)C(=O)O
Agent: B
Agent: CCB(CC)CC
Solvent: C1CCOC1
Product: CC(N)(CCCO)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 133.3 %

Procedure:
Finely ground racemic a-methylglutamic acid (5.0 g, 0.029 mol) was suspended in THF (30 mL), treated with triethylborane (1M in THF, 32.32 mL, 0.032 mol), and heated at reflux for 36 h. After cooling to 0° C. the soln was treated dropwise with borane in THF (1M, 35.26 mL, 0.035 mol) and stirred at 0° C. for 3 h. The mixture was quenched with 5% aq HCl (30 mL), stirred for 0.5 h, concentrated on a rotary evaporator, and the residue dissolved in 5% HCl (44 mL) and heated at reflux for 0.75 h. After cooling and concentrating, the residue was taken up in MeOH (50 mL), concentrated, and this procedure repeated 3×to give 5.69 g of the title compound which was not purified.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH:5]=[N:6][OH:7].[Cl:10]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:7][N:6]=[C:5]([Cl:10])[C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: C[Si](C)(C)C#CC=NO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)C#CC(Cl)=NO
Reaction time: 4 h

Procedure:
To a solution of 3-trimethylsilylprop-2-ynal oxime (Carreira, Erick M.; Lohse-Fraefel, Nina, Organic Letters, Volume 7, Issue 10, 2005, Pages 2011-20141, 68 g, 11.9 mmol) in 11.9 mL of DMF stirred at r.t. was added N-chlorosuccinimide (1.99 g, 14.8 mmol). After 4 h stirring, the solution was poured into water and extracted with Et2O. After the usual work-up, the residue (2.09 g) was used as it was for the next step.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnn2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Fluorobenzonitrile (0.847 g, 7 mmol), 1H-[1,2,3]triazole (0.483 g, 7 mmol), Cs2CO3 (2.27 g, 7 mmol) and DMF (8 ml) and a magnetic stirrer were placed in a vial. The mixture was heated with stirring for 3 h at 80° C. Extractive work-up (EtOAc/H2O) and subsequent drying (Na2SO4) gave a crude product which was purified on silica giving 0.55 g (46%) of the title intermediate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.O[C:26]1[CH:58]=[CH:57][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:56])=[CH:28][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[C:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][N:11]3[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=[C:3]3[CH2:2][O:1][C:26]3[CH:58]=[CH:57][C:29]([CH2:30][CH:31]4[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]4=[O:56])=[CH:28][CH:27]=3)=[CH:14][CH:15]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1nc2cccnc2n1Cc1ccc(-c2ccccc2)cc1
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(OCc3nc4cccnc4n3Cc3ccc(-c4ccccc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 2-hydroxymethyl-3-(4-phenylbenzyl)-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 54), 0.738 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.43 ml of tributylphosphine, 0.4 g of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:2 to 1:3 by volume as the eluent, to give 0.95 g of the title compound having Rf=0.44 (on silica gel thin layer chromatography using a 1:3 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)C.CO.O1CCCC1.O.[OH-].[Li+]>O>[F:14][C:13]([F:15])([F:16])[C:10]1[CH:11]=[CH:12][C:7]([NH:6][CH2:5][C:4]([OH:17])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CNc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a stirred solution of (4-trifluoromethyl-phenylamino)-acetic acid ethyl ester (0.37 g, 1.5 mmol) in a mixed solvent of methanol (10 mL), tetrahydrofuran (10 mL), and water (10 mL) was added lithium hydroxide monohydrate (0.25 g, 6 mmol) and the mixture was stirred at room temperature overnight. The organic solvent was removed under reduced pressure and the aqueous solution was acidified with solid citric acid to pH˜4, and extracted with ethyl acetate (4×40 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to give 0.33 g of the crude title compound that was used direct for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ: 12.68 (s, 1H), 7.38 (d, 2H), 6.66 (d, 2H), 3.87 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[CH3:26].COC(=O)CC1C2C(=NC=CC=2Cl)NC=1C.[H-].[Na+].CS(C1C=CC(CBr)=CC=1)(=O)=O>CN(C=O)C.O>[Cl:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[C:6]([CH3:26])=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[C:13]=12
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2)c2nccc(Cl)c12
Agent: COC(=O)Cc1c(C)[nH]c2nccc(Cl)c12
Agent: CS(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2c(Cl)ccnc2n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
[4-Chloro-1-(4-methanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To a cooled (0° C.) stirred solution of (4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.1 g, 0.42 mmol) in dry DMF (2.5 ml) is added sodium hydride (0.019 g of a 60% dispersion in mineral oil, 0.47 mmol). After stirring at room temperature for 5 hours, the reaction mixture is re-cooled to 0° C. and treated with 4-methylsulfonylbenzyl bromide (0.105 g, 0.42 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is diluted with water (3 ml) and extracted with ether (3×15 ml). The organic portions are combined, washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting crude residue is loaded on a pre-packed Isolute™ silica column and eluted with iso-hexane:ethyl acetate (1:8) to yield the titled compound as a white powder. (MH+ 407).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([OH:22])=O)[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C.[NH2:55][C:56]1[C:61]([CH2:62][CH2:63][C@H:64]2[O:69][CH2:68][C@@H:67]([CH2:70][O:71][Si:72]([C:75]([CH3:78])([CH3:77])[CH3:76])([CH3:74])[CH3:73])[N:66]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:65]2)=[CH:60][CH:59]=[CH:58][N:57]=1>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Si:72]([O:71][CH2:70][C@H:67]1[N:66]([C:79]([O:81][C:82]([CH3:83])([CH3:84])[CH3:85])=[O:80])[CH2:65][C@@H:64]([CH2:63][CH2:62][C:61]2[C:56]([NH:55][C:20](=[O:22])[C@H:6]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:5][C:3]([O:2][CH3:1])=[O:4])=[N:57][CH:58]=[CH:59][CH:60]=2)[O:69][CH2:68]1)([C:75]([CH3:76])([CH3:77])[CH3:78])([CH3:73])[CH3:74]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2cccnc2N)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)Nc1ncccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CO1)C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (1.1 eq.) in DMF (0.15 M) at rt were added HATU (1.4 eq.) and 2,6-lutidine (3 eq.). The reaction mixture was stirred for 30 min and tert-butyl (2R,5S)-2-[2-(2-aminopyridin-3-yl)ethyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate (1 eq) was added. The reaction mixture was stirred at 60° C. for 16 h and diluted with EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound. Alternatively, DMF could be replaced as solvent by pyridine to ease coupling involving less reactive amine.
Reaction SMILES: Br[CH:2]([CH:7](Br)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[C:3]([O:5][CH3:6])=[O:4].[OH-].[K+].[CH2:27](O)C>>[N:21]1[CH:22]=[CH:23][C:18]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:7]#[C:2][C:3]([O:5][CH2:6][CH3:27])=[O:4])[CH:9]=3)[N:14]=[CH:13][CH:12]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(Br)C(Br)c1ccc2nccc(-c3ccncc3)c2c1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C#Cc1ccc2nccc(-c3ccncc3)c2c1
Temperature: 95 °C
Yield: 60 %

Procedure:
A slurry of methyl 2,3-dibromo-3-[4-(4-pyridinyl)-6-quinolinyl]propanoate (4.20 g, 9.33 mmol) in ethanol (120 ml) was treated with solid potassium hydroxide pellets in one portion then heated at 95° C. for 2 hours. The reaction was cooled to room temperature then evaporated under reduced pressure. The resulting residue was diluted with ethanol (90 ml) and concentrated H2SO4 (3 ml) then heated at 95° C. for 3.5 hours. Cooled to room temperature then concentrated under reduced pressure. The resulting wet residue was taken into a minimum of water then made neutral with the addition of saturated aqueous NaHCO3 solution. This solution was extracted with EtOAc and the extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc) to give the title compound (1.68 g, 60%) as a pale yellow solid. MS (ES)+ m/e 303 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1OC1C>C(COC)OC>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]3[N:3]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:1]=3)=[CH:8][CH:7]=1
Reactant: COc1ccc2ccc(N)nc2c1
Reactant: CCOC(=O)C(=O)CBr
Agent: CC1CO1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(ccc3ccc(OC)cc32)n1
Reaction time: 16 h

Procedure:
50 ml of 2-amino-7-methoxyquinoline [C.A., Vol. 79, p. 92024t] were dissolved in 50 ml of dimethoxyethane and then a mixture of 3 g of ethyl bromopyruvate and 1 g of propylene oxide in 5 ml of dimethoxyethane was added thereto. The mixture was allowed to stand at 5° C. for 16 hours and the intermediate quaternary salt thus precipitated was filtered off, washed with diethyl ether and then was dissolved in 50 ml of ethanol. The solution was refluxed for 1 hour and then was reduced in volume under vacuum. Diethyl ether was subsequently added thereto to precipitate ethyl 8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate hydrobromide which was filtered off and was washed with diethyl ether. The hydrobromide was partitioned between 50 ml of dilute sodium carbonate solution and 100 ml of chloroform and the organic solution was separated, washed with 50 ml of water, was dried over MgSO4 and was evaporated to dryness under reduced pressure. The residue was crystallized from diethyl ether to obtain buff crystals of ethyl 8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 146°-148° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[C:3]1([CH3:10])[CH3:9].Cl[C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=2)[C:3]1([CH3:10])[CH3:9]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC1(C)C(N)CCCC1O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(NC2CCCC(O)C2(C)C)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
A mixture of 3-amino-2,2-dimethylcyclohexanol (1.30 g, crude) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.35 g, 7.27 mmol), and DIEA (1.93 g, 15.0 mmol) in isopropanol (14 mL) was stirred at 90° C. for 1 h. After removal of the solvent, the residue was purified by silica gel column chromatography (10%-30% ethyl acetate in petroleum ether) to afford the title compound (820 mg, 2.81 mmol, 38% yield), which was separated by chiral column (Superchiral S-AD, 0.46 cm I.D.×25 cm L, 5 μl, CO2/MeOH/DEA=80/20/0.05 (v/v/v); Flow: 2.5 ml/min, 254 nm, T=35° C.), then by chiral column: Chiralpak IC, 0.46 cm I.D.×25 cm L, 5 μl, CO2/MeOH/DEA=70/30/0.05 (v/v/v); Flow: 2.5 ml/min, 254 nm, T=35° C.) to give four isomers (peak 1: 90 mg, d.e.=100%, e.e.=100%, peak 2: 220 mg, d.e.=99.7%, e.e.=100%, peak 3: 210 mg, d.e.=100%, e.e.=97.3%, peak 4:125 mg, d.e.=99.6%, e.e.=100%. Peak 1 and peak 4 were determinated to be cis-isomers and peak 2 and peak 3 were determinated to be trans-isomers by 2D-NMR). MS (ESI) m/z 293.1 [M+H]+
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:25][CH3:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[ClH:35]>O1CCCC1.O>[OH2:2].[ClH:35].[OH:2][CH2:1][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:25][CH3:26])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:15])=[CH:11][CH:12]=1.[OH:2][CH2:1][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:25][CH3:26])[CH3:15])=[CH:11][CH:12]=1.[ClH:35]
Reactant: COC(=O)COc1ccc(CC(C)NCC(OC)c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COC(CNC(C)Cc1ccc(OCCO)cc1)c1ccccc1

Procedure:
N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-methoxy-2-phenylethanamine (3.09 g) in dry tetrahydrofuran (30 ml) was added dropwise, with stirring, to a suspension of lithium aluminium hydride (1.65 g) in dry tetrahydrofuran (40 ml) and the resultant mixture heated under reflux for five hours. After cooling, water (1.7 ml), 10% aqueous sodium hydroxide (1.7 ml) and water (3.4 ml) were added carefully. Filtration and evaporation of the filtrate to dryness gave an oil which was converted to its hydrochloride salt by addition of ethereal hydrogen chloride. Crystallisation from methanol-ethyl acetate gave the title compound, mp 100°-2° C., as a 90:10 mixture of diastereoisomers.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[O:41][CH:40]=[N:39][CH:38]=3)=[C:33]([OH:42])[CH:32]=2)=[O:29])=[C:26](Br)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[O:41][CH:40]=[N:39][CH:38]=3)=[C:33]([OH:42])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Nc1ncnc(Br)c1C(=O)Nc1ccc(-c2cnco2)c(O)c1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Nc3ccc(-c4cnco4)c(O)c3)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 1.4 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.37 mmol), 4-amino-6-bromo-N-(3-hydroxy-4-(oxazol-5-yl)phenyl)pyrimidine-5-carboxamide (220 mg, 0.58 mmol), DIEA (325 μl, 1.87 mmol) and cesium fluoride (113 mg, 0.74 mmol) were suspended in tert-butanol (10 ml) and the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate and washed with water and brine. After evaporation of the solvent, the residue was purified by reverse phase using SP1® Purification System to give 3 mg (1% yield) of the title compound as a solid. Purity 97%.