Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: BrCCc1ccccc1
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CC#N
Product: O=Cc1cc(Cl)ccc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
5 g of 5-chlorosalicylaldehyde was dissolved in 300 ml of acetonitrile. After adding 41.48 g of potassium fluoride/alumina (neutral) (2:3) and 17.45 ml of (2-bromoethyl)benzene, the resulting mixture was stirred at room temperature for 63 hours. Then the potassium fluoride/alumina was removed by filtration under sucking and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=10:1) and recrystallized from isopropyl ether to give 5.58 g of 5-chloro-2-(2-phenylethoxy)benzaldehyde.
Reaction SMILES: [C:1]([CH2:3][C:4](=S)[NH2:5])#[N:2].BrCC.[O-]CC.[Na+].[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([OH:19])=O>>[Cl:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:15]2[C:16]=1[C:17](=[O:19])[N:5]=[C:4]([CH2:3][C:1]#[N:2])[NH:14]2
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: N#CCC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCBr
Product: N#CCc1nc(=O)c2c(Cl)cccc2[nH]1
Reaction time: 6 h
Yield: 23.2 %

Procedure:
2-cyanoethanethioamide (300 mg, 3.00 mmol) and bromoethane (261 μL, 3.50 mmol) were added to an ethanolic solution of sodium ethoxide (3.50 mmol, 2.5 mL). The resulting mixture was stirred for 6 hours, 2-amino-6-chlorobenzoic acid (500 mg, 2.91 mmol) was added, and the reaction was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with ethanol, water, ethanol, and diethyl ether. The solid was then dried to yield 2-(5-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (148 mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.15 (s, 2H), 7.54 (dd, J1=7.8 Hz, J2=1.1 Hz, 1H), 7.61 (dd, J1=8.2 Hz, J2=1.1 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: COc1cccc([C@H](C)Nc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc([C@H](C)Nc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 91.5 %

Procedure:
To a solution of 2,5-dichloro-N-[(1S)-1-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.70 g, 2.3 mmol) and 3-aminobenzyl alcohol (0.39 g, 3.2 mmol) in 1,4-dioxane (20.0 mL) was added p-toluenesulfonic acid monohydrate (0.16 g, 0.85 mmol). The mixture was heated at 100° C. for 16 hours and NaHCO3 (saturated aqueous solution) was added. The organic solvent was removed under vacuum and water/EtOAc was added. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown powder (0.81 g, 90%). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]1)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:52]1[C:57](=[O:58])[CH2:56][CH2:55][C:53]1=[O:54])=[N+](C)C)C>C1COCC1.C(#N)C>[O:54]=[C:53]1[CH2:55][CH2:56][C:57](=[O:58])[N:52]1[O:37][C:36]([CH:33]1[CH2:34][CH2:35][CH:30]([CH2:29][NH:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:31][CH2:32]1)=[O:38]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)O)CC1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Yield: 87.8 %

Procedure:
To a solution of 4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarboxylic acid (5.56 g) in THF (100 ml) was added a solution of TSTU (3.42 g) in acetonitrile (25 ml). The mixture was concentrated in vacuo after stirring over night. The solid residue was recrystallized from acetonitrite to give 4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarboxylic acid 2,5-dioxopyrrolidin-1-yl ester (5.76 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][OH:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[CH:11][N:10]=[CH:9]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[CH:11][N:10]=[CH:9]1
Reactant: Cc1cncn1-c1ccc(N2C[C@H](CO)OC2=O)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cncn1-c1ccc(N2C[C@H](COS(C)(=O)=O)OC2=O)cc1F
Reaction time: 18 h
Yield: 62.2 %

Procedure:
3-(3-Fluoro-4-(5-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (0.86 g, 2.96 mmol) was stirred in a mixture of pyridine (30 ml) and triethylaminc (0.36 g, 3.55 mmol) under nitrogen in an ice-bath. Methanesulfonyl chloride (0.37 g, 3.26 mmol) was added dropwise, and the mixture stirrd for 18 hours, allowing the temperature to rise to ambient. Solvent was evaporated. and the residue dissolved in dichloromethane (50 ml), and washed with aqueous sodium bicarbonate (5%, 25 ml), water (2×25 ml), brine (20 ml), and dried (magnesium sulfate). The residue after evaporation was triturated with diethyl ether to give the title product (0.68 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([CH2:40]O)[CH:34]=[CH:33]2.O>C(Cl)Cl>[Br:20][CH2:40][C:35]1[CH:34]=[CH:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([C:24]3[C:23]([Cl:22])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:29])[CH:31]=2)[CH:36]=1
Reactant: BrBr
Reactant: OCc1ccc2cc(-c3c(Cl)cccc3Cl)ccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1ccc2cc(CBr)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of PPh3 (0.251 g) in CH2Cl2 (1 ml) is added drop by drop, at 0° C., a solution of bromine (0.049 ml) in CH2Cl2 (1 ml). After 30 min, [6-(2,6-dichlorophenyl)-2-naphthyl]methanol 287 (0.242 g) is added. The mixture is stirred, under argon, at RT for 6 h. Water (2 ml) is added. The aqueous phase is extracted with CH2Cl2 (3×5 ml). The organic phases are dried over MgSO4 and evaporated under vacuum. The residue is purified by silica gel chromatography using AcOEt/cyclohexane 40/60 as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([CH3:28])[CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C>C(O)C>[CH3:28][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[C:24]=1[N+:25]([O-:27])=[O:26]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccnc(Nc2ccc3[nH]cc(CC4CCCN4C)c3c2)c1[N+](=O)[O-]
Yield: 34 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 2-chloro-4-methyl-3-nitropyridine were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 24 hours. Column chromatography afforded the title compound (34%) as a red amorphous solid: 1H NMR (CDCl3) δ9.26 (brs, NH),8.79 (brs, NH),8.10 (d,J=4.8 Hz, 1H), 7.64(d,J=1.7 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.5 and 1.9 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.56 (d, J=4.8 Hz, 1H), 3.25-3.16 (m, 2H), 2.67 (dd, J=13.2 and 9.4 Hz, 1H), 2.64-2.56 (m, 1H), 2.56 (s, 3H), 2.46 (s, 3H), 2.30 (dd, J=17.7 and 9.4 Hz, 1H), 1.90-1.60 (m, 4H); 13C NMR (CDCl3) δ152.2, 151.5, 146.6, 134.3, 131.0, 130.0, 127.9, 123.4, 119.4, 117.1, 114.0, 113.3, 111.6, 67.0, 57.4, 40.7, 31.4, 29.5, 21.8, 21.7; FAB HRMS calculated for [C20H23N5O2.H]366.1932, found 366.1957.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=O)[CH3:2].[Br:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.C1(=O)CCCCC1.N1CCOCC1.[S]>>[NH2:20][C:19]1[S:5][C:6]2[CH2:2][CH2:1][CH2:4][CH2:8][C:7]=2[C:18]=1[C:16]([C:14]1[S:15][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: N#CCC(=O)c1ccc(Br)s1
Agent: [S]
Solvent: C1COCCN1
Solvent: O=C1CCCCC1
Product: Nc1sc2c(c1C(=O)c1ccc(Br)s1)CCCC2
Yield: 66 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-bromothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-bromothiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclohexanone (Aldrich), 2-(5-bromothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 66%; IR (KBr) cm−1: 3379, 3247, 2918, 1577, 1548, 1432, 1416, 1273, 761; 1H NMR (CDCl3):δ1.63 (m, 2H), 1.79 (m, 2H), 2.24 (t, 2H, J=5.8 Hz), 2.55 (t, 2H, J=5.8 Hz), 6.11 (bs, 2H), 7.02 (d, 1H, J=4 Hz), 7.13 (d, 1H, J=4 Hz); orange solid, mp: 160-163° C. (petroleum ether).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)([F:4])[CH3:3].C(N)CN>CO.[Pd]>[F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])([F:4])[CH3:3]
Reactant: CC(F)(F)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: NCCN
Solvent: CO
Product: CC(F)(F)c1cccc(N)c1
Reaction time: 5.5 h
Yield: 95.3 %

Procedure:
To a solution of 1-(1,1-difluoroethyl)-3-nitrobenzene (1.00 g, 5.34 mmol) in methanol (5.0 mL) was added Pd/C (catalytic amount) and ethylene diamine (catalytic amount). The reaction mixture was subjected for hydrogenation in Parr apparatus under 30 psi for 5-6 h. The excess of solvent was removed under vacuum to afford 0.800 g of the desired product. 1HNMR (DMSO-d6): δ 1.88 (d, J=18.0 Hz, 3H), 3.74 (s, 1H), 7.72 (t, J=8.4 Hz, 1H), 6.81 (s, 1H), 6.87 (d, J=7.8 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:10]=[C:9]([C:19]([OH:21])=O)[CH2:8]2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:10]=[C:9]([C:19]([Cl:24])=[O:21])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1
Reaction time: 2 h

Procedure:
5-(5-Bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (18.1 g, 46.9 mmol) prepared in Step 4 was added to thionyl chloride (200.0 mL). The reaction mixture was stitted at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(5-bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.C([O:41][C:42]1[CH:47]=[C:46]([CH2:48]Br)[CH:45]=[CH:44][C:43]=1[C:50]#[N:51])(=O)C>CC#N>[NH2:51][CH2:50][C:43]1[CH:44]=[CH:45][C:46]([CH2:48][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:47][C:42]=1[OH:41]
Reactant: CC(=O)Oc1cc(CBr)ccc1C#N
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1O
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.375 g, 0.99 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.35 mL, 2.00 mmol) followed by a solution of (5-bromomethyl-2-cyano-phenyl) acetate (0.318 g, 1.25 mmol) in CH3CN (5 mL). The resultant mixture was heated to 60° C. for 15 hours then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (40 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2—CH30H) followed by radial chromatography on silica gel (2 mm plate, 2:1 hexanes-EtOAc) provided 0.28 g (51%) of a tan foam.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 73.6 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (772 mg, 4 mmol), aniline (364 μL, 4 mmol) and DIEA (838 μL, 24.8 mmol) in 10 mL THF was stirred at r.t. for 70 h. After removal of the solvent, the residue was dissolved in DCM, and subjected to silica gel column purification to give 735 mg (yield 74%) of the title compound. LC-MS: Calculated mass=249. Observed mass=250.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[F:1][C:2]1[N:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: Cc1cnc(F)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(C)cnc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
To a solution of 2-fluoro-5-methylnicotinic acid (4.9 g, 31.6 mmol), N,O-dimethylhydroxylamine hydrochloride (4.01 g, 41.08 mmol), diisopropylethylamine (12.6 ml, 72.68 mmol) in dichloromethane (150 ml) at 0° C. was added TBTU (11.16 g, 34.76 mmol) portionwise over 30 minutes. The solution was stirred at 0° C. for a further 10 minutes then, at room temperature for 18 hours. The reaction mixture was washed with a 10 wt % solution of citric acid and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion□, 80 g column, 0-20% EtOAc/Petrol) to afford the title compound as a colourless solid (5.44 g, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=432.1, tR (minutes, Method F)=2.6
Reaction SMILES: [C:1]1([CH:7]([NH2:15])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]1[CH2:20][CH2:19][N:18]=[C:17]1S(O)(=O)=O>CC(O)CC.O>[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[N:15][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1
Reactant: NC(Cc1ccncc1)c1ccccc1
Reactant: O=S(=O)(O)C1=NCCN1
Solvent: CCC(C)O
Solvent: O
Product: c1ccc(C(Cc2ccncc2)N=C2NCCN2)cc1
Temperature: 110 °C

Procedure:
A mixture of 1-phenyl-2-(pyridin-4-yl)ethanamine (0.23 g, 1.18 mmol), and 4,5-dihydro-1H-imidazole-2-sulfonic acid (0.18 g, 1.16 mmol) in 2-butanol (5 mL), water (1 mL) were heated at 110° C. for 3 hours. The solution was cooled to room temperature. The solvents were removed under vacuum. The residue was dissolved in methanol, and added amino modified silica gel. The solvent was removed under vacuum. Purification by chromatography on amino modified silica gel (100% ethyl acetate to 7% methanol in dichloromethane) gave N-(imidazolidin-2-ylidene)-1-phenyl-2-(pyridin-4-yl)ethanamine Compound 3 as a while solid (0.21 g, 0.80 mmol, 67% yield).
Reaction SMILES: [N+:1]([C:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[NH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[N:24]=[CH:23][N:22]=1.O>CN(C=O)C>[CH3:29][O:28][C:25]1[N:24]=[CH:23][N:22]=[C:21]([CH2:20][N:6]2[C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)[C:26]=1[CH3:27]
Reactant: O=[N+]([O-])c1c[nH]c2cccnc12
Reactant: COc1ncnc(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncnc(Cn2cc([N+](=O)[O-])c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a stirred suspension of 3-Nitro-1H-pyrrolo[3,2-b]pyridine (25b) (0.5 g, 3.04 mmol) and K2CO3 (0.5 g, 9.12 mmol) in DMF (10 mL) was added 4-(chloromethyl)-6-methoxy-5-methylpyrimidine (0.7 g, 6.09 mmol) and the resulting mixture was stirred for 16 h at room temperature. Then the reaction mixture was poured in to water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with brine and the solvent was evaporated under reduced pressure to yield 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-3-nitro-1H-pyrrolo[3,2-b]pyridine (25c) [300 mg (33%)] as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:19]#[N:20])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1(c2ccc(Cl)cc2)CCCC1
Temperature: 130 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (320) (14 g, 48.48 mmol) in dimethyl sulfoxide (50 mL) were added KI (805 mg, 4.85 mmol) and NaCN (3.6 g, 72.72 mmol) and stirred for 130° C. for 4 h. After completion of reaction, cold water (200 mL) was added. After extraction with ethyl acetate (3×100 mL), the combined organic parts were washed with saturated ferrous sulphate solution (2×100 mL), water (2×100 mL) and brine (100 mL) and dried and concentrated. The crude product was purified by CombiFlash column (10-20% ethyl acetate in hexane was used as eluent) to get [1-(4-chlorophenyl)-cyclopentyl]-acetonitrile (321) (8.2 g, 77%) as a light yellow liquid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C@@H:12]1[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]1)([CH3:11])([CH3:10])[CH3:9].[F:19][CH:20]([C:22]1[C:27]([Cl:28])=[C:26](Cl)[N:25]2[N:30]=[CH:31][N:32]=[C:24]2[N:23]=1)[CH3:21]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:8]([C@@H:12]1[CH2:13][CH2:14][C@H:15]([NH:18][C:26]2[N:25]3[N:30]=[CH:31][N:32]=[C:24]3[N:23]=[C:22]([CH:20]([F:19])[CH3:21])[C:27]=2[Cl:28])[CH2:16][CH2:17]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(F)c1nc2ncnn2c(Cl)c1Cl
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(F)c1nc2ncnn2c(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl

Procedure:
0.220 g (2.2 mmol) Triethylamine, a spatula tip of tetrabutylammonium iodide and 0.340 g (2.2 mmol) of cis-4-tert-butylcyclohexylamine were added successively to a solution of 0.470 g (2.0 mmol) of 5-(1-fluoroethyl)-6,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine in 15 ml of toluene under stirring. The reaction mixture was heated at reflux for 5 hours and then stirred for another 12 hours at room temperature. The solvent was evaporated under reduced pressure and dichloromethane was added to the resulting residue. The resulting reaction mixture was washed with 2N hydrochloric acid and water. The organic phase was separated, dried and the solvent was evaporated under reduced pressure. Treatment of the resulting residue with hexane yielded 0.540 g (1.5 mmol, 76% of theory) of the title compound having a melting point of 138-139° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([OH:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(N(C(C)C)CC)(C)C.C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]([OH:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:27](=[O:28])[CH2:26][Cl:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: OC(CCNCc1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)N(CCC(O)(c1ccccc1)c1ccccc1)Cc1ccccc1

Procedure:
To the stirred solution of 15.6 g of N-benzyl-3-hydroxy-3,3-diphenylpropylamine in 7.0 g of di-isopropylethylamine and 150 ml of methylene chloride, that of 5.88 g of chloroacetyl chloride in 50 ml of methylene chloride is added dropwise while stirring and cooling with an ice-bath. Thereupon the solution is stirred for 15 minutes at 0°-5° and washed successively with N hydrochloric acid, 10% aqueous sodium bicarbonate and finally with saturated aqueous sodium chloride. The organic layer is separated, dried, filtered and evaporated, to yield the N-benzyl-N-chloroacetyl-3-hydroxy-3,3-diphenylpropylamine showing in the I.R.-spectrum a strong band at 1640 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:15]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:21])=[CH:9][CH:10]=3)[C:5](=[O:22])[C:4]=2[CH:3]=1.[CH3:23][Mg]Cl.BrC1C=CC2OC3C(=NC(Cl)=CC=3F)C(=C)C=2C=1>C1COCC1>[Br:1][C:2]1[C:15]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:21])=[CH:9][CH:10]=3)[C:5]([CH3:23])([OH:22])[C:4]=2[CH:3]=1
Reactant: C[Mg]Cl
Reactant: O=c1c2cc(I)ccc2oc2cc(OC(F)(F)F)c(Br)cc12
Agent: C=C1c2cc(Br)ccc2Oc2c(F)cc(Cl)nc21
Solvent: C1CCOC1
Product: CC1(O)c2cc(I)ccc2Oc2cc(OC(F)(F)F)c(Br)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
A RBF was charged with 2-bromo-7-iodo-3-(trifluoromethoxy)-9H-xanthen-9-one (2.94 g, 6.06 mmol) and THF (33.7 mL). The black suspension was cooled to −78° C. using an i-PrOH/dry ice bath. Methylmagnesium chloride (3.0 M in THF, 4.45 mL, 13.34 mmol) was added dropwise. After 2 h, LCMS showed olefin product. The whole was quenched with satd' aq NH4Cl (20 mL) at 0° C., water (50 mL) and diluted with EtOAc (100 mL). The product was extracted with EtOAc (3×50 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to afford yellow oil. 1H NMR confirmed the tertiary alcohol, 2-bromo-7-iodo-9-methyl-3-(trifluoromethoxy)-9H-xanthen-9-ol (3.04 g, 6.07 mmol, 100% yield). LCMS (ESI) calcd for C15H9BrF3IO3: [M]+=500. Found [M−H2O+H]+=483. Dehydration took place on LCMS to give the olefin, 2-bromo-7-iodo-9-methylene-3-(trifluoromethoxy)-9H-xanthene). This material was carried on to the next step.