Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:5]([OH:6])[C@H:4](/[CH:7]=[CH:8]/[C@@H:9]([OH:22])[CH2:10][O:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][CH:13]=2)[C@@H:3]([CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C@H:2]1[OH:32].[NH2:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40]>CO.O>[CH3:35][CH:34]([O:30][C:29]([CH2:28][CH2:27][CH2:26]/[CH:25]=[CH:24]\[CH2:23][C@@H:3]1[C@@H:4](/[CH:7]=[CH:8]/[C@@H:9]([OH:22])[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)[C@H:5]([OH:6])[CH2:1][C@@H:2]1[OH:32])=[O:31])[CH3:42].[NH2:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O
Solvent: CO
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Reaction time: 0.5 h

Procedure:
To travoprost free acid ((+)-fluprostenol free acid) 3 in MeOH/H2O was added L-Arginine (>98%) (Sigma-Aldrich Cat. A5006) and the solution was stirred for 30 minutes. The solvents were evaporated then azeotroped with Et2O and hexanes to give white crystalline travoprost-L-Arginine salt 4 (quantitative).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65](=[O:73])[NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:69])=[O:68])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:52][CH2:51]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56](O)=[O:57])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.[CH:75]12[NH:82][CH:79]([CH2:80][CH2:81]1)[CH2:78][O:77][CH2:76]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65]([NH:66][S:67]([CH:70]([CH3:71])[CH3:72])(=[O:68])=[O:69])=[O:73])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:51][CH2:52]5)[N:48]=[C:47]([CH:53]([CH3:54])[CH3:55])[C:46]=4[C:56]([N:82]4[CH:75]5[CH2:81][CH2:80][CH:79]4[CH2:78][O:77][CH2:76]5)=[O:57])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CC2COCC1N2
Reactant: COc1ccc2c(c1)C=C(c1c(C(=O)O)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(c1c(C(=O)N3C4CCC3COC4)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reaction time: 2 h
Yield: 33.3 %

Procedure:
HATU (65.0 mg, 0.171 mmol) was added to a stirring solution of 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.114 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (34 mg, 0.23 mmol), DIEA (80 μL, 0.456 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to stir for 2 hours. The reaction was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/MeOH gradient, and concentrated to give the titled compound (30 mg, 0.038 mmol, 34% yield) consistent by LCMS and NMR, with sufficient purity by HPLC.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22]([NH:24][NH2:25])=[O:23])[N:6]=1)([CH3:4])[CH3:3].[OH-].[K+].[C:28](=[S:30])=S>CO>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:20])([CH3:19])[CH3:21])[N:8]=[C:7]([C:22]2[O:23][C:28](=[S:30])[NH:25][N:24]=2)[N:6]=1)([CH3:1])[CH3:3]
Reactant: S=C=S
Reactant: COCCOCOc1c(C(C)(C)C)nc(C(=O)NN)nc1C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1nc(-c2n[nH]c(=S)o2)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
4,6-Bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxylic acid hydrazide (0.9 g, 2.5 moles), KOH (0.16 g, 2.8 moles), and carbon disulfide (0.44 g, 5.8 mmoles) are dissolved in 20 mL of MeOH. The reaction mixture is warmed to reflux under argon for 24 hours. It is cooled to room temperature, quenched with 150 mL of 10% HOAc/H2O, and extracted with ether (3×100 mL). The ether extract is washed with brine (3×100 mL) and evaporated. The oil remaining is taken up in 20 mL of TFA and stirred at room temperature for 30 minutes. The TFA is evaporated on the rotovap, and the oil is partitioned between 100 mL of ether and 100 mL of H2O. The pH of the water layer is adjusted to 5 by the addition of saturated sodium bicarbonate. The layers are separated and the organic layer is washed with 50 mL of brine. Drying over MgSO4 and evaporation of solvent gives a yellow oil. Flash chromatography in 50% Et2O/hexane followed by two recrystallizations from Et2O/hexane gives 0.16 g (20%) of 5-[ 4,6-bis (1,1-dimethylethyl) -5-hydroxy-2-pyrimidinyl ]-1,3,4-oxadiazole-2(3H )-thione, 234°-236° C. dec. Analysis for C14H20N4O2S: Calcd.: C, 54.52; H, 6.54; N, 18.17; S, 10.40. Found: C, 54.46; H, 6.40; N, 18.38; S, 10.53.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[C:23]5[CH2:31][CH2:30][NH:29][CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH2:68]([N:70]([CH2:76][CH3:77])[CH2:71][CH2:72][C:73](O)=[O:74])[CH3:69]>CN(C=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[C:23]5[CH2:31][CH2:30][N:29]([C:73](=[O:74])[CH2:72][CH2:71][N:70]([CH2:76][CH3:77])[CH2:68][CH3:69])[CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(CC)CCC(=O)O
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CCNC4)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, Example 31-C, (120 mg, 0.26 mmol), HATU (198 mg, 0.52 mmol), DIEA (0.2 mL, 1.30 mmol) and DMF (5 mL) is added 3-diethylamino-propionic acid hydrochloride (47 mg, 0.26 mmol). After stirring at rt for 2 h the contents of the flask are partitioned between DCM and 10% aqueous LiCl. Organic layer is removed, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is then separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 581.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.40-8.48 (m, 1 H), 8.33 (d, J=8.8 Hz, 1 H), 8.06 (s, 1 H), 7.94 (d, J=3.5 Hz, 1 H), 7.89 (d, J=8.6 Hz, 1 H), 7.57 (t, J=8.1 Hz, 1 H), 7.36-7.47 (m, 2 H), 7.10 (dd, J=9.0, 2.1 Hz, 1 H), 6.74 (d, J=3.8 Hz, 1 H), 4.71-4.79 (m, 2 H), 3.85-4.05 (m, 2 H), 3.20 (d, J=5.8 Hz, 2 H), 2.84-3.08 (m, 8 H), 1.23 (q, J=7.1 Hz, 6 H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:12][CH3:13]
Reactant: CCCBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccccc1C=O
Temperature: 25 °C
Reaction time: 21.5 h
Yield: 94.3 %

Procedure:
To salicylaldehyde (12.2 g) dissolved in DMF (100 ml) were added 1-bromopropane (14.7 g) and potassium carbonate (20.7 g), and the resulting mixture was stirred at room temperature for 21.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 2-propoxybenzaldehyde (15.47 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[S:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[N:32]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][C:46]=2[CH3:52])[N:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([S:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:37])[N:32]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][C:46]=2[CH3:52])[N:31]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c(C)c1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4C)c3)c2cc1OC
Yield: 77 %

Procedure:
The title compound was prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 230A (94 mg, 0.27 mmol) and phenyl 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-ylcarbamate (120 mg, 0.33 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea (130 mg, 0.21 mmol, 77%). 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.68 (s, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.43-7.38 (m, 2H), 7.36 (s, 1H), 7.32 (s, 1H), 7.25-7.16 (m, 4H), 6.34 (s, 1H), 4.33 (t, 2H), 3.99 (s, 3H), 3.76 (t, 2H), 3.34 (s, 3H), 2.37 (s, 3H), 1.95 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 627 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][N:8]=[C:7]([S:15]([CH3:17])=[O:16])[C:6]2=[O:18].[OH-].[Na+].[CH3:21]OS(OC)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:21])[N:8]=[C:7]([S:15]([CH3:17])=[O:16])[C:6]2=[O:18]
Reactant: COS(=O)(=O)OC
Reactant: COc1cc2[nH]nc(S(C)=O)c(=O)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(=O)c(S(C)=O)nn(C)c2cc1OC

Procedure:
A solution of 10 g of 6,7-dimethoxy-3-(methylsulfinyl)-4(1H)-cinnolinone in 148 ml of 1 normal NaOH was treated with 14 g of (CH3)2SO4 with stirring. As the (CH3)2SO4 dissolved, the temperature rose to ca. 35° and a pasty precipitate formed. The mixture was stirred for 45 minutes and the precipitate was filtered off, washed with cold H2O and recrystallized from CH3CN, mp. 262°-64°; yield 6 g (57%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.O[CH2:22][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=4)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(CNC(=O)OC(C)(C)C)c3)C2=O)cn1
Yield: 89.2 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (070 mg, 0.254 mmol), tert-butyl 3-(hydroxymethyl)benzylcarbamate (0.254 mmol, 60 mg), diethyl azodicarboxylate (0.50 mmol, 86 mg), and P-tBu3 (125 mL, 0.50 mmol) were stirred in THF (1 mL) for 4 hours. The reaction was diluted with ethyl acetate (1.5 mL) and washed with saturated sodium bicarbonate solution (2×, 1.5 mL). The organic phase was collected and the mixture was concentrated under a stream of nitrogen. The crude product was purified by column chromatography on silica gel using ethyl acetate as the eluent. The pure fractions were combined and the solvents were removed on the rotovap to afford tert-butyl 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzylcarbamate as a white solid (112 mg, 90%). 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 9H), 2.19 (s, 3H), 2.42 (s, 3H), 3.48 (bs, 1H), 3.84 (s, 2H), 4.31-4.30 (d, J=6 Hz, 1H), 4.60 (s, 2H), 4.87 (bs, 1H), 5.06 (s, 2H), 7.36-7.16 (m, 4H), 7.92 (s, 1 H), 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.90 μM.
Reaction SMILES: CCN(CC)CC.[C:8]([O:16][CH2:17][C:18]#[CH:19])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:20](=[N:22]/[OH:23])\[CH3:21]>C(Cl)(Cl)Cl>[C:8]([O:16][CH2:17][C:18]1[O:23][N:22]=[C:20]([CH3:21])[CH:19]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CCOC(=O)c1ccccc1
Reactant: C/C=N/O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(COC(=O)c2ccccc2)on1
Reaction time: 8 h

Procedure:
To a solution of chloroform, Et3N (0.435 mL, 3.12 mmol), prop-2-ynyl benzoate (1 g, 6.24 mmol), and (E)-acetaldehyde oxime (0.571 mL, 9.37 mmol) at 0° C. was added bleach (23.12 mL, 18.73 mmol). The reaction was stirred overnight before the layers were separated and the aqueous extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (3-methylisoxazol-5-yl)methyl benzoate. LC/MS m/z 218 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[Cl:18][C:19]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[Cl:18][C:19]1[CH:26]=[C:25]([CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])[O:27][CH:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=1)[C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: O=Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccc(C=O)c(Cl)c1)c1ccccc1
Yield: 76.3 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 4, 1.00 g (6.41 mmol) of 2-chloro-4-hydroxybenzaldehyde was alkylated with 1.61 g (7.05 mmol) of methyl 2-bromophenylacetate to afford 1.49 g (76%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH:24]=[O:25])=[CH:4][CH:3]=1.C[Si](C)(C)[C:30]([F:33])([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH:24]([OH:25])[C:30]([F:33])([F:32])[F:31])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCC(C=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(O)C(F)(F)F
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a stirred solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butanal (51.8 mg, 0.123 mmol) and trimethyl(trifluoromethyl)silane (54.3 μL, 0.368 mmol) in tetrahydrofuran (0.6 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 12.3 μL, 0.0123 mmol) at 0° C. After 30 min, hydrochloric acid (1.0 M, 0.25 mL) was added. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless oil (49.0 mg, 0.0995 mmol, 81%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16](=O)[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1.Cl.[CH3:28][O:29][C:30]1[C:35]([CH3:36])=[CH:34][N:33]=[C:32]([CH2:37][NH:38][NH2:39])[C:31]=1[CH3:40]>ClCCl>[Cl:26][C:11]1[N:10]=[C:9]([NH2:8])[N:14]=[C:13]2[N:38]([CH2:37][C:32]3[C:31]([CH3:40])=[C:30]([O:29][CH3:28])[C:35]([CH3:36])=[CH:34][N:33]=3)[N:39]=[C:16]([CH2:17][CH:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)[C:12]=12
Reactant: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Reactant: COc1c(C)cnc(CNN)c1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N)nc32)c1C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of triethylamine (3.44 mL) in dehydrated dichloromethane was added to a mixture composed of 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-one of 3) above (1.68 g), [(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-hydrazine hydrochloride of 4) above (2.87 g) and dehydrated dichloromethane (60 mL) under cooling in an ice bath over 20 minutes. The ice bath was removed, followed by stirring for two hours. Then, the reaction mixture was separated with chloroform and water. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain the title compound (1.79 g, 75%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].O.[NH2:10][NH2:11]>CCO>[CH:7]1[CH:8]=[C:3](/[C:1](/[NH2:2])=[N:10]\[NH2:11])[N:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: N#Cc1ccccn1
Solvent: CCO
Solvent: O
Product: N/N=C(/N)c1ccccn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 137.5 %

Procedure:
2-Cyano pyridine (500 mg, 1.923 mmol) and Hydrazine hydrate (252 mg, 1.923 mmol) were mixed together in EtOH (3 ml). The clear solution was left at 15° C. (in refrigerator) for 18 h (Monitored by TLC). Ethanol was concentrated under reduced pressure and then the reaction mixture was diluted with diethyl ether (50 ml) and water. The diethyl ether layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to 1/5th Volume. The ethereal solution was cooled to 0° C. and the obtained solid precipitate was collected over the filtration and dried under vacuum, which gave the 2-pyridine Amidrazone (360 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]2[S:9][CH:10]=[C:11]([C:12](O)=[O:13])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]2[S:9][CH:10]=[C:11]([C:12]([Cl:19])=[O:13])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2scc(C(=O)O)c2c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2scc(C(=O)Cl)c2c1

Procedure:
5-Acetoxybenzo[b]thiophene-3-carboxylic acid (12) (1,349 mg) prepared above was refluxed for 1.5 hours with dimethylformamide (1 drop), thionyl chloride (1.22 ml) and toluene (25 ml). The solvent was removed under reduced pressure to provide 1,454 mg of the title compound (13).
Reaction SMILES: CN([CH:4]([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14])=O)C.[NH2:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[F:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[CH:4]=[CH:15][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH3:24])[N:16]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(C(=O)c1cccc(F)c1F)N(C)C
Product: CCOC(=O)c1ccc(-c2cccc(F)c2F)nc1C

Procedure:
The title compound was prepared from dimethylamino-(2,3-difluorophenyl)-propan-1-one and ethyl 3-aminocrotonate using the general procedure outlined in D18. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.28 (d, 1H), 7.83 (m, 1H), 7.70 (dd, 1H), 7.22 (m, 2H), 4.41 (q, 2H), 2.91 (s, 3H), 1.42 (t, 3H).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C:14]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[O:15])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([N:18]2[CH2:19][CH2:20][O:21][CH:16]([C:14]([NH:13][C@@H:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH3:12])=[O:15])[CH2:17]2)[CH:26]=[CH:27][CH:28]=1
Reactant: C[C@@H](NC(=O)C1CNCCO1)c1cccc2ccccc12
Reactant: Fc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)C1CN(c2cccc(F)c2)CCO1)c1cccc2ccccc12
Temperature: 110 °C

Procedure:
A mixture solution of N-((R)-1-(naphthalen-1-yl)ethyl)morpholine-2-carboxamide (Intermediate-2) (300 mg, 1.056 mmol) in toluene (10 mL), bis(tri-tert butyl phosphine) Pd(0) (0.10, 54 mg), trisdibenzylidene acetone dipalladium(0) (48 mg, 0.0528 mmol), 1-fluoro-3-iodobenzene (0.15 ml, 1.26 mmol) and Cs2CO3 (516 mg, 1.58 mmol) were added. The reaction mass was heated to 110° C. and further maintained for 15 h under nitrogen atmosphere. The mixture was diluted with ethyl acetate, filtered through celite bed, and concentrated under vacuum. It was further purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as eluent to afford title compound as oily mass (250 mg), m/z: 379.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:17]1([CH:23]2[CH2:24][CH2:25][N:26]([CH:14]3[C:15]4[C:10](=[N:9][C:8]5[C:3]([C:2]=4[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:11][CH2:12][CH2:13]3)[CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1c2c(nc3ccccc13)CCCC2N1CCC(c2ccccc2)CC1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed for 48 hours in 300 ml of toluene that contained 4-phenylpiperidine (8.06 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was concentrated and the residue purified by flash chromatography (5% Et3N/toluene) to give, after concentration of theproduct-containing fractions and recrystallization from EtOAc/pentane, 3.22g of analytically pure product, m.p. 189°-190°.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:15])=[CH:10][C:11]=3[C:12](=[S:14])[NH:13][C:4]=2[CH:3]=1.[CH3:18]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>CC(OC)(C)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:15])=[CH:10][C:11]=3[C:12]([S:14][CH3:18])=[N:13][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Nc1ccc(Cl)cc1NC2=S
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: COC(C)(C)C
Product: CSC1=Nc2cc(Cl)ccc2Nc2sc(C)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
Stir 7-chloro-2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (59.1 g, 0.210 mol) and DMF (236.4 mL) under nitrogen for 15 minutes at ambient temperature. Add powdered potassium carbonate (61.1 g, 0.442 mol); stir 15 minutes at ambient temperature. Add iodomethane (26.2 mL, 0.421 mol) and stir 2.5 hours at ambient temperature. Add MTBE (591 mL) and stir 15 minutes at ambient temperature. Filter and rinse solids with MTBE (59.1 mL). Wash the organic filtrate with water (3×591 mL), then dry over sodium sulfate, filter and concentrate under reduced pressure to give 60.0 g (96.7%) of crude product. 1H NMR (500 MHz, DMSO-d6) δ 2.22 (s, 3H), 2.39 (s, 3H), 6.47 (d, 1H), 6.57 (d, 1H), 6.86 (d, 1H), 6.97(dd, 1H), 8.09 (bs, 1H). 13C NMR (100 MHz, DMSO-d6) δ 13.24, 14.70, 120.58, 120.62, 121.67, 125.64, 127.51, 127.52, 127.77, 141.65, 142.16, 153.99, 165.48.