Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1.[CH2:27]=[O:28]>CCCCC.C1COCC1>[Si:20]([O:19][CH:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:27][OH:28])=[CH:8][CH:9]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reactant: C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
tert-Butyllithium (6.6 mL of a 1.7 M solution in pentane, 11.32 mmol) was added to a solution of the aryl bromide 7 (2.0 g, 5.39 mmol) in THF (22 mL) at −78° C. After 0.5 h paraformaldehyde (323 mg, 8.09 mmol) was added. The reaction was warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 6:1 hex/EtOAc) yielded 1.2 g (69%) of the alcohol 8 as a clear, colorless oil.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20](=[O:36])[CH2:19][C:18]=2[CH2:37][C:38]2[O:42][C:41]([C:43]([O:45]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:44])=[CH:40][CH:39]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:43]([C:41]1[O:42][C:38]([CH2:37][C:18]2[CH2:19][S:20](=[O:36])[C@@H:21]3[C@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:23](=[O:35])[N:22]3[C:17]=2[C:15]([OH:16])=[O:14])=[CH:39][CH:40]=1)([OH:45])=[O:44]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cc3ccc(C(=O)OC(c4ccccc4)c4ccccc4)o3)CS(=O)[C@H]12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cc3ccc(C(=O)O)o3)CS(=O)[C@H]12

Procedure:
By treating 0.70 g of 3-(5-diphenylmethoxycarbonylfurfuryl)-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid diphenylmethyl ester 1-oxide with 5 ml of trifluoroacetic acid and 2 ml of anisole, the 3-(5-carboxy-furfuryl)-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid 1-oxide is obtained; thin-layer chromatogram (silica gel): Rf = 0.15 (system: n-butanol/ethanol/water 40:10:50).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([O:68][C:69]([N:71]1[CH2:76][CH2:75][N:74]([C:77](=[O:87])[C@@H:78]([NH2:86])[CH2:79][CH2:80][C:81]2[N:82]=[N:83][NH:84][N:85]=2)[CH2:73][CH2:72]1)=[O:70])[CH2:65][CH2:66][CH3:67]>CN(C=O)C>[CH2:64]([O:68][C:69]([N:71]1[CH2:72][CH2:73][N:74]([C:77](=[O:87])[C@@H:78]([NH:86][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:29])[CH2:79][CH2:80][C:81]2[N:85]=[N:84][NH:83][N:82]=2)[CH2:75][CH2:76]1)=[O:70])[CH2:65][CH2:66][CH3:67]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nn[nH]n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 327 mg 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 5 ml DMF were added 415 μl DIPEA, 302 mg HATU and 360 mg 4-[(S)-2-amino-4-(2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate. After 30 minutes the reaction mixture was concentrated and the crude product obtained purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 180 mg
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].C(O)CO.[C:12]1(C)[CH:17]=CC(S(O)(=O)=O)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.O.C(C(C)=O)C>[CH3:17][C:12]([CH2:13][CH3:14])=[CH:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)CCCBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: OCCO
Solvent: O
Product: CCC(C)=CCCC(C)=O

Procedure:
To a solution of 20.9 g. of the ethylene ketal of 1-bromo-4-pentanone (obtained by treating 1-bromo-4-pentanone with ethylene glycol in benzene in the presence of p-toluenesulfonic acid) in 100 ml. of benzene is added 20 g. of triphenylphosphine. The mixture is heated at reflux temperature for two hours and then filtered. The solid material thus-collected is washed with benzene, dried in vacuo and added to 6.49 g. of butyl lithium in 50 ml. of dimethylsulfoxide. The mixture is stirred until an orange solution is obtained and 38 g. of methyl ethyl ketone is then added. The mixture is stirred at about 25° for about eight hours, poured into water and then extracted with ether. The ethereal phase is concentrated and the concentrate added to 0.1N solution of hydrochloric acid in aqueous acetone and stirred for about 15 hours. The mixture is then poured into ice water and extracted with ethyl acetate. The extracts are combined, washed with water, dried over sodium sulfate and evaporated to yield 6-methyl-5-octen-2-one which is purified by chromatography and separated into the cis and trans isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Br)=[O:10])=[CH:4][CH:3]=1.[C:12]([S-:14])#[N:13].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([S:14][C:12]#[N:13])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Br)Cc1ccc(Cl)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSC(=O)Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
4-Chlorophenylacetyl bromide (12.2 g, 52.3 mmol) was suspended in ethanol (50 ml) and heated to 60° C.–70° C. An aqueous solution (10 ml) of KSCN (5.59 g, 57.5 mmol) was added by small portions, and after addition, the mixture was stirred at 80° C. for 10 min. The reaction mixture was left standing at room temperature for 4 hrs. Water (150 ml) was added and the precipitated solid was collected by filtration. The residue was washed twice with water (150 ml) and dried under reduced pressure to give the title compound (10.1 g, 91%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.CCN(C(C)C)C(C)C.[C:18]([C:20]1[CH:21]=[C:22]([CH3:27])[C:23](F)=[N:24][CH:25]=1)#[N:19]>C(O)CCC.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:23]1[C:22]([CH3:27])=[CH:21][C:20]([C:18]#[N:19])=[CH:25][N:24]=1
Reactant: COCC1CCCN1
Reactant: Cc1cc(C#N)cnc1F
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CCCN1c1ncc(C#N)cc1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
2-(Methoxymethyl)pyrrolidine (Acb-blocks C5A-0029; 406 mg; 3.53 mmol; 1.2 eq.) and DIEA (1.52 ml; 8.82 mmol; 3 eq.) were added to a solution of 5-cyano-2-fluoro-3-methylpyridine (400 mg; 2.94 mmol; 1 eq.) in 1-butanol (1 mL) and the reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was allowed to return to room temperature then diluted with ethyl acetate, washed with water, dried over magnesium sulphate and concentrated in vacuo to afford the title compound (0.59 g, 87%) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35][CH2:36]O)[CH3:23]>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:36][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: CCc1sc(-c2ccccc2)nc1CCO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Product: CCc1sc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 94 %

Procedure:
Intermediate 57 was prepared as described above for the preparation of intermediate 52. From 575 mg of N-(Boc)-L-Tyrosine methyl ester and 500 mg of Intermediate 9B was prepared 940 mg of BOC-protected intermediate methyl ester (94% yield; 1H NMR (DMSO-d6, 300 MHz) δ7.93 (m, 2H), 7.47-7.41 (m, 3H), 7.04 (d, 2H, J=8.4), 6.86 (d, 2H, J=8.6), 4.96 (d, 1H, J=4.56 (m, 1H), 4.34 (t, 2H, J=6.8), 3.73 (s, 3H), 3.23 (t, 2H, J=6.9), 3.04 (m, 2H), 2.90 (q, 2H, J=7.5), 1.44 (s, 9H), 1.37 (t, 3H, J=7.5)); From 900 mg of protected intermediate was prepared 900 mg of intermediate 57 as a solid. 1H NMR (DMSO-d6, 300 MHz) δ8.16 (br s, 2H), 7.85 (m, 2H), 7.5-7.43 (m, 3H), 7.14 (d, 2H, J=8.6), 6.90 (d, 2H, J=8.6), 4.27 (t, 2H, J=6.5), 4.12 (m, 1H), 3.12 (t, 2H, J=6.5), 3.0 (m, 2H), 2.86 (q, 2H, J=7.5), 1.26 (t, 3H, J=7.5).
Reaction SMILES: C1COCC1.[OH-].[Na+].C([O:15][C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:17])C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH2:29]([O:28][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C:16]([OH:17])=[O:15])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)c1ccc2ccccc2c1OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2ccccc2c1OCc1ccccc1

Procedure:
Method slightly modified, THF (30 mL) instead of MeOH and 5M NaOH (32 mL) were added to the rbf containing compound 1-Benzyloxy-naphthalene-2-carboxylic acid benzyl ester (1.40 g, 3.80 mmol). A condenser was added and the mixture was refluxed for 9 hours. The mixture was diluted with H2O (100 mL) and citric acid (17.70 g, 92.12 mmol) was added to pH-4. Extracted with CH2Cl2 (3×100 mL), washed with H2O (2×150 mL) and saturated NaCl (1×150 mL). NMR showed final product with small percent of starting material. Purification was achieved by recrystallization in hexanes (2×20 mL). Solvent removed under pressure and concentrated in vacuo. Yield: 0.652 g of white crystals (62%). 1H NMR (400 MHz, CDCl3) δ 5.24 (s, 2H), δ 7.43-7.54 (m, 3H), δ 7.61-7.68 (m, 2H), δ 7.75 (d, J=8.7 Hz, 1H), δ 7.93 (dd, J=7.3 Hz, 1 Hz, 1H), δ 8.10 (d, J=8.7 Hz, 1H), δ 8.25 (d, J=7.8 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Cl.ClC[C:46]1[N:50](C)[N:49]=[CH:48][N:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:50]([CH3:46])[N:49]=[CH:48][N:47]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Cn1ncnc1CCl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cl
Product: Cn1ncnc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride and isolated as colorless gum. MS (m/e): 378.3 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([NH:36][CH2:37][CH2:38][OH:39])[C:34]=1[Cl:35])[C:30]#[N:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:35][C:34]1[C:33]([NH:36][CH2:37][CH2:38][OH:39])=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:19][CH2:20]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: N#Cc1cc(N)c(Cl)c(NCCO)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(NCCO)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 60 °C
Yield: 34.6 %

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (126 mg, 0.354 mmol), 3-amino-4-chloro-5-((2-hydroxyethyl)amino)benzonitrile (75 mg, 0.354 mmol), palladium(II) acetate (21.08 mg, 0.094 mmol), XANTPHOS (20.50 mg, 0.035 mmol), DPPF (19.65 mg, 0.035 mmol) and cesium carbonate (300 mg, 0.921 mmol) in Dioxane (3 mL) was evacuated and back filled with nitrogen three time and was heated at 60° C. for 1 h. The reaction mixture was filtered through a pad of Celite, rinsed with EtOAc and the filtrate was concentrated. Purification via flash chromatography (0-70% EtOAc in Hexane, 24 g) gave 2-((2-chloro-5-cyano-3-((2-hydroxyethyl)amino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (65 mg) as a light yellow foam.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.ClC1C2N(C(CCC)=NN=2)[C:23]2[C:28]([N:29]=1)=[CH:27][CH:26]=[CH:25]C=2>>[CH2:15]([C:12]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([NH:29][CH:28]4[CH2:27][CH2:26][CH2:25][CH2:23]4)[C:3]2=[N:14][N:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1nnc2c(Cl)nc3ccccc3n12
Reactant: CCCCc1nnc2c(Cl)nc3ccccc3n12
Product: CCCCc1nnc2c(NC3CCCC3)nc3ccccc3n12

Procedure:
The title compound was prepared essentially as described in Example 4 substituting 4-chloro-1-butyl[1,2,4]triazolo[4,3-a]quinoxaline for 4-chloro-1-propyl[1,2,4]triazolo[4,3-a]quinoxaline; mp 195°-197° C.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)C>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: Nc1ccccc1F
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2F)[nH]c1=O
Reaction time: 24 h
Yield: 17.4 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (20 g) and 2-fluoroaniline (15.6 g) are added to ethanol (200 ml), and the mixture is refluxed with stirring for 24 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-fluoroanilino)-6-oxo-5-pyrimidinecarboxylate (4.5 g). M.p. 250°-252° C.
Reaction SMILES: [Li+].[OH-].[CH2:3]([N:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([O:18]C)=[O:17])[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C1COCC1.CO>[CH2:3]([N:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[C:11]1=[O:20])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1nccn(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nccn(Cc2ccccc2)c1=O
Reaction time: 4 h
Yield: 81.6 %

Procedure:
LiOH (0.82 mL, 0.82 mmol, 1.0 M) was added to a solution of methyl 4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylate (0.10 g, 0.41 mmol) in a mixture of THF-MeOH (3:1 ratio, 6 mL) at room temperature. After stirring for 4 hours, 1 N HCl (0.9 mL) was added. The reaction mixture was extracted with EtOAc, dried over MgSO4, and concentrated to give the desired product (0.077 g, 82%). 1H NMR (400 MHz, CD3OD) δ 8.0 (d, 1H), 7.68 (d, 1H), 7.36-7.42 (m, 5H), 5.29 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:33])[CH3:32])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.00 g, 3.18 mmol) in 15 mL of CH2Cl2 was placed under an atmosphere of nitrogen. The solution was chilled in an ice water bath and treated first with triethylamine (0.89 mL, 6.7 mmol) and then slowly with acetyl chloride (0.89 mL, 3.3 mmol). After 2 h, the reaction was warmed to ambient temperature, quenched with 15 mL of saturated NaHCO3 solution and diluted with 30 mL of CHCl3. The phases were separated and the organic portion was washed with H2O (15 mL) and brine (15 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow foam. The foam was crystallized from MeCN to give light yellow crystals. The crystals were pulverized and then triturated with Et2O for 18 h and filtered off to yield N-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)acetamide (0.728 g) as a white solid. mp 178–181° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.44 (d, J=8.1 Hz, 1H), 7.82 (t, J=5.1 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.45–7.42 (m, 1H), 7.26–7.22 (m, 1H), 6.96 (t, J=5.6 Hz, 1H), 6.59 (s, 2H), 4.75 (s, 2H), 3.61 (q, J=7.0 Hz, 2H), 3.20–3.14 (m, 4H), 1.77 (s, 3H), 1.71 (p, J=7.0 Hz, 2H), 1.17 (t, J=7.0Hz, 3H);
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4([NH:44]C(=O)OC(C)(C)C)[CH2:43][CH2:42][CH2:41]4)=[CH:36][CH:35]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][O:25][CH:24]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:52].O1CCOCC1>C(Cl)Cl.CO>[ClH:52].[ClH:52].[ClH:52].[NH2:44][C:40]1([C:37]2[CH:36]=[CH:35][C:34]([N:33]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([N:22]6[CH2:27][CH2:26][O:25][CH:24]([C:28]([N:29]([CH3:31])[CH3:30])=[O:32])[CH2:23]6)[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:39][CH:38]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: CN(C)C(=O)C1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)CCO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C(=O)C1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(N)CCC6)cc5)c4n3)c2)CCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[2-(dimethylcarbamoyl)morpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (25.6 mg, 0.0372 mmol) was dissolved in DCM (1 mL)-MeOH (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 1.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (25.6 mg, 98.6%) as yellow solid.
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:6].[Cl-].[NH4+]>C(OC)(C)(C)C.O1CCCC1>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([OH:6])([CH3:2])[CH3:4])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
The reaction flask was charged under argon with 3.45 g of magnesium (142 mmol). A solution of 21.16 g of methyl iodide (147 mmol) in 120 mL of tert-butyl-methyl-ether was added during 45 minutes at 45° C. under stirring. Then stirring was continued for 1 hour at 45° C. and then a solution of 27.12 g of 4-benzyloxyacetophenone (120 mmol) in 100 mL of tetrahydrofuran was added during 45 minutes, while a temperature of 45° C. was again maintained. Stirring at 45° C. was continued for 1.5 hours. After cooling to room temperature, the white suspension was poured into a mixture of 100 mL of 10% aqueous ammonium chloride and of ice and extracted with 150 mL of ethyl acetate. The aqueous phase was separated and extracted with 100 mL of ethyl acetate. The organic phase was washed with 120 mL of 20% aq. sodium chloride, combined, dried (MgSO4) and evaporated under reduced pressure to give 29.9 g of crude product as an oil which partially crystallised. The crude product was taken up in 30 mL of dichloromethane. The solution was concentrated at the rotary evaporator almost to dryness. Then 6 mL of ethyl acetate was added followed by gradual addition of a total of 180 mL of hexane. The suspension was then kept at 0° C. for 30 minutes. The crystals were collected and washed with cold hexane. After drying for 2 hours at 16 mbar/45° C., 26.7 g (92%) 2-(4-benzyloxy-phenyl)-propan-2-ol was obtained.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].IC.CN1C(=O)N(C)CCC1>C1COCC1.[Cl-].[Na+].O>[C:1]([C:9]1([CH3:22])[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2)C1
Reactant: C[Si](C)(C)[NH-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A stirred solution of (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (409 mg, 1.42 mmol) in dry THF (15 mL) under N2 was cooled to −78° C. A solution of lithium bis(trimethylsilylamide) in THF (2.84 mL of 1.0M, 2.84 mmol, 2 equiv) was added dropwise. After 30 min, a solution of iodomethane (220 μL, 3.5 mmol, 2.5 equiv) in DMPU (512 μL, 4.24 mmol, 3.0 equiv) was added slowly. After 15 min, the reaction mixture was allowed to warm to rt and stirred overnight. LC-MS showed the reaction was complete. Brine (50 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4. After concentration, the crude product was purified by chromatography on a prepacked 12-g silica gel cartridge eluted with a 0-35% EtOAc in hexanes gradient to afford tert-butyl 3-benzoyl-3-methylpiperidine-1-carboxylate (278 mg, 65%). LC-MS (3 min) tR=1.92 min, m/z 326 (M+Na).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([NH:31][C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([O:39][CH2:40][CH2:41][CH3:42])[CH:33]=3)=[O:30])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH2:40]([O:39][C:34]1[CH:33]=[C:32]([NH:31][C:29]([N:26]2[CH2:27][CH2:28][N:23]([S:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:2]4[C:11]5[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:19][CH:18]=3)(=[O:21])=[O:22])[CH2:24][CH2:25]2)=[O:30])[CH:37]=[C:36]([F:38])[CH:35]=1)[CH2:41][CH3:42]
Reactant: CCCOc1cc(F)cc(NC(=O)N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)c1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: CCCOc1cc(F)cc(NC(=O)N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)c1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)-sulfonyl]-4-[[(3-propoxy-5-fluorophenyl)amino]-carbonyl]piperazine to give 1-[[(3-propoxy-5-fluorophenyl)amino]carbonyl]-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.