Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C)C.[C:5]([O:9][C:10](=[O:23])[NH:11][CH2:12][CH2:13][N:14]1[CH2:21][CH:20]2[O:22][CH:16]([CH2:17][NH:18][CH2:19]2)[CH2:15]1)([CH3:8])([CH3:7])[CH3:6].[O:24]1[CH2:26][C@H:25]1[CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>O>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([O:28][CH2:27][C@@H:25]([OH:24])[CH2:26][N:18]2[CH2:17][CH:16]3[O:22][CH:20]([CH2:21][N:14]([CH2:13][CH2:12][NH:11][C:10](=[O:23])[O:9][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:15]3)[CH2:19]2)=[CH:30][CH:31]=1)#[N:34]
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Reactant: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCN1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Temperature: 66 °C
Yield: 99.4 %

Procedure:
iso-Propanol (5 mL) and water (0.5 mL) were added to [2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butyl ester (see Example 3 (Alternative I) above; 0.43 g, 1.6 mmol) and 0.4-[(2S)-oxiranylmethoxy]benzonitrile(0.280 g, 1.6 mmol; see Preparation D above) was added. The mixture was heated at 66° C. for 19 hours (reaction was complete in 2 hours). The solvent was evaporated to dryness under reduced pressure to give the title compound as an off-white solid (0.71 g, 100%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:22][CH3:23])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:24])[CH:3]=1.[NH3:25]>CO>[CH2:22]([C:9]1[C:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:24])[CH:3]=[C:2]([NH2:25])[N:7]2[N:8]=1)[CH3:23]
Reactant: CCc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(OC)cc1
Reactant: N
Solvent: CO
Product: CCc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(OC)cc1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-2-ethyl-3-(4-methoxy-benzenesulphonyl)-5-methyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 2-ethyl-3-(4-methoxy-benzenesulphonyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 186-188°.
Reaction SMILES: Cl[Si:2]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[O:3][Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6].[CH2:18]([O:25][C@H:26]1[C:30](=[CH2:31])[C@H:29]([CH2:32][OH:33])[C@H:28]([OH:34])[C@@H:27]1[OH:35])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:18]([O:25][C@@H:26]1[C@@H:27]([OH:35])[C@@H:28]2[O:34][Si:2]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[O:3][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[O:33][CH2:32][C@H:29]2[C:30]1=[CH2:31])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Reactant: C=C1[C@H](CO)[C@H](O)[C@H](O)[C@H]1OCc1ccccc1
Solvent: c1ccncc1
Product: C=C1[C@@H]2CO[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)O[C@H]2[C@H](O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane (5.5 mL, 16.8 mmol) was added dropwise to a solution of triol 5 (4.0 g, 16.0 mmol) in anhydrous pyridine at −30° C. The reaction mixture was allowed to warm up to room temperature gradually and kept at the same temperature for 2 h. After removing the pyridine in vacuo, the residue was dissolved in EtOAc and washed with H2O and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on a silica gel (EtOAc:Hexanes=1:30 to 1:5) to yield the alcohol 6 (6.5 g, 82%) as a syrup. [α]24D −105.94° (c 0.58, CHCl3); 1H NMR (500 MHz, CDCl3) δ7.41-7.26 (m, 5H), 5.36 (t, J=2.5 Hz, 1H), 5.11 (t, J=2.5 Hz, 1H), 4.77 (d, J=12.0 Hz, 1H), 4.62 (d, J=12.5 Hz, 1H), 4.18-4.14 (m, 2H), 4.05 (dd, J=4.5 and 12.0 Hz, 1H), 3.78 (dd, J=8.0 and 12.0 Hz, 1H), 2.90-2.88 (m, 1H), 1.08-0.97 (m, 27H); 13C NMR (125 MHz, CDCl3) δ 147.3, 138.1, 128.4, 127.6, 127.5, 111.1, 80.2, 74.2, 71.2, 71.1, 64.9, 50.1, 17.6, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0. Anal. Calcd. for C26H44O5Si2: C, 63.37; H, 9.00. Found: C, 63.64; H, 9.05.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:22]1[S:23][CH:24]=[CH:25][C:21]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCc1ccsc1Br
Reaction time: 24 h
Yield: 94.8 %

Procedure:
A solution of N-bromosuccinimide (NBS) (48 g; 0.27 mol) dissolved in DMF (160 ml) was added dropwise to 3-dodecylthiophene (68 g; 0.27 mol) dissolved in DMF (110 ml). The reaction solution was stirred for one day, 750 ml of water was added thereto. An organic material was extracted from ethyl ether (3×300 ml), washed with brine and water, and then the residual moisture was removed over anhydrous magnesium sulfate. After removing the solvent, the residue was distilled off under reduced pressure at 125° C./˜5 mmHg to obtain a product (84.85 g, yield of 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[OH:19].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:16][C:13]([F:14])([F:15])[C:8]([C:6]1[CH:5]=[C:4]([CH3:18])[C:3]([O:19][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:2]([CH3:1])[CH:7]=1)([OH:17])[C:9]([F:10])([F:11])[F:12]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Reaction time: 5 h

Procedure:
To 2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)phenol [Farah, et al, J. Org. Chem., 30, 1003 (1965)], (10.0 g=35 mmol) in 100 ml acetonitrile add ethyl bromoacetate (6.9 g=42 mmol) and potassium carbonate (9.7 g=69 mmol). Stir 5 hours, filter and concentrate. Partition between ether and 1.0 N HCl. Dry and concentrate the ether extract. Recrystallize from ether-hexane to obtain, as white crystals, m.p. 99°-101° C., ethyl 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:23][C:5]=1[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[CH3:2].[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:7]([CH2:6][C:5]1[CH:23]=[C:24]([C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[CH:25]=[CH:26][C:4]=1[O:3][CH2:1][CH3:2])[CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:10][CH2:9]1)=[O:41]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: CCOc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2ccc(C)nc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 75 (373 mg, 0.82 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (227 mg, 1.80 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2-].[Na+].[CH:3]1[CH2:5][CH:4]=1.I[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].C(O)C>N.CCOCC>[CH2:14]([C:3]1[CH2:5][CH:4]=1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH2:7]
Reactant: C=CCCCCCCI
Reactant: C1=CC1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: C=CCCCCCCC1=CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of 0.43 g (11 mmol) of sodium amide in roughly 15 ml of ammonia was cooled to −78° C. A chilled solution of cyclopropene in ammonia (1:1, 0.85 g, 10 mmol) was poured into the reaction mixture. The reaction mixture was stirred at −78° C. for ½ hour, warmed briefly to the ammonia boiling point, then recooled to −78° C. 8-Iodooct-1-ene (1.2 g, 5 mmol) was added by syringe, and the reaction mixture was warmed to reflux for ½ hour. A few ml of ethanol were added. Ether (25 ml) was slowly added while the ammonia was allowed to distill out of the reaction mixture. The reaction mixture was washed with water, 0.5M HCl (2×), water and brine. It was dried over MgSO4, filtered and stripped. The product was purified by chromatography on silica gel using hexane as the eluent. A 10 mg sample of 67% pure 1-(oct-7-enyl)-cyclopropene was obtained.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[CH3:6][C:7]([CH3:44])([CH2:40][C:41]#[C:42][CH3:43])[C@H:8]([O:33]C1CCCCO1)/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:15]([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:14](=[O:25])[CH2:13][C@H:12]1[O:26]C1CCCCO1>C(O)(=O)C.O.C1COCC1>[CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[CH3:6][C:7]([CH3:44])([CH2:40][C:41]#[C:42][CH3:43])[C@H:8]([OH:33])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:15]([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:14](=[O:25])[CH2:13][C@H:12]1[OH:26]
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Agent: CS(N)(=O)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
At 25°, 400 mg. of (5Z,13E)-(11R,15R)-16,16-dimethyl-9-oxo-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid methylsulfonamide is agitated for 16 hours with 12 ml. of a mixture of glacial acetic acid/water/THF (65/35/10). The mixture is evaporated under vacuum and the residue purified by column chromatography on silica gel. With methylene chloride/2-5% methanol 202 mg. of the title compound is obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[I:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[CH3:52])[NH2:48]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:48][C:47]1[CH:49]=[CH:50][C:51]([CH3:52])=[C:45]([I:44])[CH:46]=1)=[O:7]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1I
Yield: 89.5 %

Procedure:
2-Chloroisonicotinic acid (3.3 g, 21 mmol), HATU (8.75 g, 23 mmol), diisopropylethyl amine (10.9 ml, 63 mmol) and 3-iodo-4-methylaniline (5.00 g, 21 mmol) in dimethylformamide (50 ml) were heated under nitrogen for 16 hours. The reaction was cooled, solvent removed in vacuo and the residue taken up in dichloromethane (150 ml). The organic solution was washed with water (3×100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (40:60 ethyl acetate:cyclohexane) to give 2-chloro-N-(3-iodo-4-methylphenyl)-isonicotinamide as a white solid (7.00 g, 18.8 mmol).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.CC1N=CNC=1[CH:19]=[O:20].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CC(O)C>[CH3:19][O:20][C:24]1[CH:23]=[CH:22][NH:21][C:26]=1/[CH:25]=[C:3]1/[C:4]2[CH:9]=[C:8]([C:10]([NH2:12])=[O:11])[S:7][C:5]=2[NH:6][C:2]/1=[O:1]
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Reactant: Cc1nc[nH]c1C=O
Reactant: C1CCNCC1
Solvent: CC(C)O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2sc(C(N)=O)cc21
Temperature: 75 °C

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (30 mg, 0.17 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). 4-Methyl-5-imidazole carboxaldehyde (0.18 mmol, 15 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (2 ml) and the precipitated solid was collected by filtration and washed with water to give 22 mg of (Z)-5,6-dihydro-4-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide as a yellow/brown solid. MS(ES): m/e 275 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:3]=1[NH2:15].[CH:16]1([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:3]=1[NH:15][C:24](=[O:25])[CH2:23][CH2:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)CCC1CCCCC1
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1C(F)(F)F
Solvent: CC#N
Product: O=C(CCC1CCCCC1)Nc1c(Br)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Yield: 33 %

Procedure:
2-Bromo-4-nitro-6-trifluoromethyl-phenylamine (2.0 g) and cyclohexylpropionyl chloride (1.30 mL) were mixed in acetonitrile (10 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction was cooled to 0° C., the product filtered off and washed with cold acetonitrile (50 mL) affording 0.97 g (33% yield) of the title compound as a yellow solid. The crude product was used without further purification. LC-MS (m/z) 424 (MH+); tR=3.53, (UV, ELSD) 95%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.88 (m, 2H), 1.17 (m, 3H), 1.28 (m, 1H), 1.51 (m, 2H), 1.68 (m, 5H), 2.38 (t, 2H), 8.45 (d, 1H), 8.82 (d, 1H), 10.17 (s, 1H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].[CH3:36][CH2:37][O:38][C:39]([CH3:41])=[O:40]>ClC(Cl)C>[C:34]([OH:33])(=[O:17])/[CH:35]=[CH:41]/[C:39]([OH:38])=[O:40].[N:1]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:37]([O:38][C:39]([N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:40])[CH3:36]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)NCCC3
Reactant: CCOC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCCc2cc3c(cc21)CCNCC3
Product: O=C(O)/C=C/C(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 200 mg of t-butyl 1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 2.13 ml of dichloroethane were added 0.553 ml of triethylamine and 0.19 ml of ethyl chloroformate, followed by stirring at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was diluted with EtOAc, washed with 1 M hydrochloric acid, water, a 1 M aqueous sodium hydroxide solution, and saturated brine, and concentrated, and the residue was purified by silica gel column chromatography (elution solvent: HEX-EtOAc). The resulting substance was dissolved in chloroform, followed by adding 0.05 ml of trifluoroacetic acid and stirring for 30 minutes. After concentration under reduced pressure, the resultant was dissolved in EtOH, neutralized by the addition of triethylamine, and then concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (elution solvent: chloroform-MeOH-aqueous ammonia). The resulting substance was dissolved in EtOH and 76 mg of fumaric acid was added thereto. The resulting white solid was collected by filtration and dried to obtain 79 mg of ethyl 2,3,4,6,7,8,9,10-octahydro-1H-azepino[4.5-g]quinoline-1-carboxylate hemifumarate.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:15]([O:17][C:18](=[O:23])[CH2:19][C:20](=[NH:22])[NH2:21])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18]([C:19]1[CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:23])=[C:20]([NH2:21])[NH:22][C:20]=1[NH2:21])=[O:23])[CH3:16]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1ccccc1-c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1-c1ccccc1
Yield: 33 %

Procedure:
Upon heating a solution of 9.1 g biphenyl-2-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 200 ml ethanol for 2 hours, 2,6-diamino-4-(biphenyl-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 215° (ethanol) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[C:6]([CH3:19])=[C:5]2[CH:20]([CH3:26])[C:21]([O:23]CC)=[O:22].C1COCC1.[OH-].[Na+].Cl>O.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=1)[C:6]([CH3:19])=[C:5]2[CH:20]([CH3:26])[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)C(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(C)C(=O)O)c2cc(Br)ccc2n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of Step 3 (11.59 g, 24.2 mmol), THF (125 mL), MeOH (60 mL), H2O (30 mL) and 10 N NaOH (10 mL) was stirred at r.t. overnight. The mixture was then acidified with 2N HCl and the product was extracted in EtOAc, the extracts were dried over Na2SO4, and the product was purified by flash chromatography on silica with EtOAc:toluene:AcOH 5:95: 1. It was then swished in ether:hexane 1:2 to yield 10.29 g, 94%, of the title product. 1H NMR (CD3COCD3) 1.50 (3H, d), 2.38 (3H, s), 4.05 (1H, q), 5.44 (2H, s), 6.95 (2H, d), 7.16 (1H, dd), 9.28 (1H, d), 7.47 (2H, d), 7.80 (1H d).
Reaction SMILES: [H-].[Na+].N#N.[Br:5][C:6]1[CH:7]=[C:8]([SH:12])[CH:9]=[CH:10][CH:11]=1.Cl[CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1>C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]([S:12][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:18][CH:19]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Sc1cccc(Br)c1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cccc(SCc2csc(-c3ccccc3)n2)c1
Reaction time: 8 h

Procedure:
NaH (53 mg, 2.2 mmol) was suspended in dry THF (1.5 ml) under a stream of N2 and 3-bromo-benzenethiol (378 mg, 2 mmol) was added dropwise to the suspension over 5 min. 4-Chloromethyl-2-phenyl-thiazole (419 mg, 2 mmol) was added and the solution left stirring overnight. The reaction mixture was quenched with a saturated K2CO3 solution (8 ml) and extracted with EtOAc (3×4 ml). The combined organic layers were washed with saturated K2CO3 solution (4 ml), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH2:23][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cc2F)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Fc1cc(-c2cnc3[nH]cc(-c4cnn(CCc5ccccc5)c4)c3c2)ccc1C1CCNCC1
Yield: 12.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (82 mg, 0.145 mmol) was deprotected in methanol/HCl in dioxane (5/5 mL) to afford 8.2 mg (12.2% yield) of the titled compound after purification by preparative TLC using 8% methanol in chloroform as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.448-8.442 (d, 1H), 8.098-8.091 (d, 1H), 7.839-7.837 (d, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.48-7.38 (m, 3H), 7.26-7.12 (m, 5H), 7.44-7.41 (t, 2H), 3.37-3.31 (m, 1H), 3.19-3.15 (t, 3H), 3.03-2.93 (td, 2H), 1.97-1.88 (m, 5H). MS: m/z=466.5 (M+1), HPLC: 98.63% in method A.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[F:14][CH:15]([F:27])[O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=O)[CH2:22]Br)=[CH:19][CH:18]=1>C(O)C>[F:14][CH:15]([F:27])[O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:22]=2)=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC(F)F)cc3)cs2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A mixture of methyl 4-thiocarbamoylbenzoate (1.56 g), 4-difluoromethoxyphenacyl bromide (2.65 g) and ethanol (15 ml) was stirred at 80 to 90° C. for 1 hour. The reaction mixture was cooled, and precipitated crystals were collected by filtration to obtain methyl 4-[4-(4-difluoromethoxyphenyl)-2-thiazolyl]benzoate (2.00 g, yield: 69%). The product was recrystallized from ethanol to obtain pale yellow prisms. Melting Point: 146 to 148° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][CH2:8][C:9]1([CH3:27])[O:13][N:12]=[C:11]([S:14][CH2:15][C:16]2[C:17]([C:23]([F:26])([F:25])[F:24])=[N:18][N:19]([CH3:22])[C:20]=2[OH:21])[CH2:10]1.[CH:28](I)([CH3:30])[CH3:29].O>CN(C)C=O.C(OCC)(=O)C>[Cl:7][CH2:8][C:9]1([CH3:27])[O:13][N:12]=[C:11]([S:14][CH2:15][C:16]2[C:17]([C:23]([F:26])([F:25])[F:24])=[N:18][N:19]([CH3:22])[C:20]=2[O:21][CH:28]([CH3:30])[CH3:29])[CH2:10]1
Reactant: CC(C)I
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1c(CSC2=NOC(C)(CCl)C2)c(C(F)(F)F)nn1C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
0.5 g (3.5 mmoles) of anhydrous potassium carbonate was added, at room temperature, into a solution of 1.0 g (2.9 mmoles) of 5-chloromethyl-3-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. Thereto was added, at room temperature, 0.6 g (3.5 mmoles) of isopropyl iodide. The mixture was stirred for 30 minutes to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.5 g (yield: 45.0%) of 5-chloromethyl-3-(1-methyl-5-isopropoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][F:11])[CH:9]=1)[CH:5]=O.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][F:11])[CH:9]=1)/[CH:5]=[N:18]/[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17]
Reactant: O=Cc1cc(F)cc(CF)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(F)cc(CF)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of 3-fluoro-5-(fluoromethyl)benzaldehyde (890 mg, 5.70 mmol) and (R)-2-methylpropane-2-sulfinamide (760 mg, 6.27 mmol) in DCE (19.0 mL) was added copper(II) sulfate (anhydrous) (1.820 g, 11.40 mmol), the suspension was stirred under nitrogen at 60° C. in an oil bath for overnight. The suspension turned to light blue color. Cooling down, the reaction mixture was filtered though a plug of Celite and rinsed with DCM, the filtrate was concentrated to yield the crude product. The crude product was purified by flash chromatograph (0-30% EtOAc in heptane) to yield the (R,E)-N-(3-fluoro-5-(fluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (900 mg, 60.9% yield) as light yellow color oil. LCMS (m/z): 260.1 (MH+), 0.88 min. 1H NMR (400 MHz, CDCl3) δ ppm 8.57 (s, 1H), 7.60 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.26-7.22 (m, 1H), 5.50 (s, 1H), 5.38 (s, 1H), 1.29-1.23 (m, 9H)