Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6](C)=[N:5]1)([CH3:3])[CH3:2].[CH3:25][C@@:26]1([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:27]5[CH2:28][CH2:29][CH2:30][C@@:26]5([CH3:25])[C:31]([NH2:33])=[O:32])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Reactant: C[C@@]1(C(N)=O)CCCN1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC[C@@]3(C)C(N)=O)cc1OCC2

Procedure:
Following the procedures for Examples 339 and 408, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and (S)-2-methyl-pyrollidine-2-carboxylic acid amide were reacted. The crude product was passed down a Isolute SCX-2 column, eluting with methanol then 2M NH3 in methanol. The basic fractions were concentrated in vacuo and the resultant residue subjected to reverse phase HPLC (C18 column, gradient 15 to 75% Methanol in water+0.1% HCO2H). The appropriate fractions were evaporated to dryness, passed down an Isolute NH2 column, eluting with methanol then further triturated in diethyl ether to give 402 as a white solid. LCMS: RT=2.79 min, [M+H]+=423. 1H NMR 400 MHz (CD3OD) δ: 9.14 (1 H, s), 7.93 (1 H, s), 7.69 (1 H, s), 6.05 (1 H, s), 5.99 (1 H, m), 4.51-4.50 (4 H, m), 3.70 (1 H, m), 3.57 (1 H, m), 3.50 (1 H, m), 2.36-2.33 (1 H, m), 2.10-2.08 (2 H, m), 1.63 (3 H, s), 1.56 (6 H, dd, J=6.63, 2.34 Hz)
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:31])[CH:9]([NH:14][C:15]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[N:21]=1)=[O:16])[C:10]([O:12][CH3:13])=[O:11].[C:32]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]3[N:21]=[C:17]([C:15]([NH:14][CH:9]([CH:8]([CH3:31])[CH3:7])[C:10]([O:12][CH3:13])=[O:11])=[O:16])[S:18][CH:19]=3)=[CH:23][CH:24]=2)=[O:41])=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)cs1)C(C)C
Reaction time: 0.08 h

Procedure:
Pyridine (0.22 ml) was added to methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 300 mg) in DCM (4 ml) and the reaction mixture was stirred for 5 minutes. 4-tert-butyl benzoyl chloride (230 mg) was added and reaction mixture was stirred for 16 hours at RT. Organic solvent was concentrated to obtain a sticky solid, which was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 235 mg (53%). 1H NMR (DMSO-d6, 300 MHz): δ 10.31 (s, 1H), 8.83 (d, 1H), 8.36 (s, 1H), 8.10 (d, 2H), 7.91 (dd, 4H), 7.56 (d, 2H), 4.38 (t, 1H), 3.68 (s, 3H), 2.35 (m, 1H), 1.31 (s, 9H), 0.98 (t, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6](CC(N2CCOCC2)=S)[CH:7]=1.[C:24]([OH:27])(=[O:26])[CH3:25].O.S(=O)(=O)(O)O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([CH2:25][C:24]([OH:27])=[O:26])[CH:7]=1
Reactant: CC(=O)O
Reactant: S=C(Cc1cc(Cl)ccc1Oc1ccccc1)N1CCOCC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: O=C(O)Cc1cc(Cl)ccc1Oc1ccccc1

Procedure:
To this morpholine residue is added 290 ml of glacial acetic acid, 61 ml of water and 87 ml of sulfuric acid (96%), and the mixture refluxed for a period of 21 hours. On cooling, the reaction mixture is dissolved in ethyl ether, washed with water until the water wash appears neutral and extracted with a 10% sodium carbonate solution. The aqueous alkaline layer is acidified with a 2 N solution of hydrochloric acid and re-extracted into diethyl ether. The ether solution is washed with water until the water washings are neutral, dried over anhydrous sodium sulfate and filtered. The solvent is removed by distillation from the filtrate and the remaining residue is crystallized from cyclohexane to yield 30.5 grams of (5-chloro-2-phenoxyphenyl)acetic acid having a m.p. of 119°-123° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: Cn1cnc2ccc(C(=O)O)cc21
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cnc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)cc21
Yield: 94 %

Procedure:
The title compound is prepared from 3-methyl-3H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 94% of theory; LC (method 4): tR=1.62 min; Mass spectrum (ESI+): m/z=332 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[Cl:21][CH:22]([Cl:26])[C:23]([OH:25])=[O:24]>>[Cl:21][C:22]([Cl:26])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:23]([OH:25])=[O:24]
Reactant: O=C(O)C(Cl)Cl
Reactant: Clc1ccc(CCCCCC#CCCCCCBr)cc1
Product: O=C(O)C(Cl)(Cl)CCCCCC#CCCCCCc1ccc(Cl)cc1
Yield: 44.6 %

Procedure:
3.90 g (11.1 mmol) 1-bromo-12-(4-chlorophenyl)-dodec-6-yne 89 was reacted with 11.4 g (89 mmol) dichloro-acetic acid analogously to example 9. 2.00 g (45%) 38 was obtained as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.O[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22]([O:14][CH2:13][CH:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4][O:5]3)=[CH:10][CH:9]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)OCCC2(C)C
Yield: 87.5 %

Procedure:
A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.366 g, 1.32 mmole) in 27 mL of THF was treated with 0.222 g of methyl 4-hydroxybenzoate, 0.382 g of triphenylphosphine and 0.23 mL of diethyl azodicarboxylate (DEAD). The reaction mixture was heated at reflux for two hours, diluted with 50 mL of ether and then washed with two 25 mL portions of water and 25 mL of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 7% ethyl acetate in hexanes) to yield 0.474 g of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoic acid methyl ester, as a pale yellow oil.
Reaction SMILES: N([CH:4]([NH2:13])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[F:12])=[N+]=[N-].[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1>[F:12][C:6]1[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:5]=1[CH:4]([NH2:13])[CH3:14]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=NC(N)c1ccc(Br)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: CC(N)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To C-Azido-C-(2-fluoro-4-bromo-phenyl)-methylamine (0.35 g, 1.43 mmol) was added triphenyl phospine (0.45 g, 1.72 mmol), 2N HCl (2 mL), and THF (2 mL). The reaction mixture was stirred at r.t. for 2 h and the reaction quenched with NaHCO3 (10 mL) and pH adjusted to 8, extracted with dichloromethane (2×30 mL) and washed with brine. The combined organic phases were dried over Na2SO4, filtered and evaporated yielding the crude product. Purification by chromatography (silica, EtOAc/Heptane, 1:1, followed by CH—2Cl2/MeOH 9:1 and with addition of a SCX colon) yielded 93 mg (30%) of 1-(2-Fluoro-4-bromo-phenyl)-ethylamine. 1H NMR δ (CDCl3): 1.44 (3H, d), 2.48 (2H, br s), 4.41 (1H, q), 7.19-7.40 (3H, m).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].[NH2:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:12]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1ccccc1F
Reaction time: 2 h

Procedure:
0.059 mL of triethylamine and 0.037 mL of 2-fluorobenzoyl chloride were added to 3.0 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially and stirred at the same temperature for 2 hours. 0.48 g of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(2-fluorobenzamido)-4-phenoxybenzoate.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21]>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:22]([CH2:23][CH:24]=[CH2:25])[CH2:19][CH:20]=[CH2:21])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Reactant: C=CCNCC=C
Product: C=CCN(CC=C)Cc1ccc([C@H]2CC[C@H](OC(C)=O)CC2)cc1

Procedure:
from trans-O-acetyl-4-(4-chloromethylphenyl)-cyclohexanol and diallylamine. Colourless oil.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].Cl[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2>O1CCCC1>[CH2:1]([O:11][C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCO
Reactant: Clc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ncnc2nc[nH]c12
Reaction time: 1 h
Yield: 61.3 %

Procedure:
1-Decanol (13ml, 68.2mmol) was added in one portion to a stirred suspension of a 60% dispersion of sodium hydride in oil (2.70 g, 67.5mmol) in dry tetrahydrofuran (70 ml) under an atmosphere of nitrogen. Gas was evolved. After 0.5 h 6-chloropurine (3.00 g, 19.4 mmol) was added and the suspension heated at reflux for 3.5 h. The tetrahydrofuran was removed in vacuo and the residue suspended in dilute hydrochloric acid (200 ml). The acidic suspension was stirred for 1 h then neutralised with saturated sodium hydrogen carbonate solution. The suspension was stirred vigorously with 60-80 petroleum ether (500 ml) and the solid removed by filtration. The solid was recrystallised from methanol to give a white solid (3.29 g, 11.9 mmol, 61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:12]1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1
Yield: 83.8 %

Procedure:
The above-described product 18a (7.87 g, 27.7 mmol) was dissolved in ethanol (50 mL), together with Pd/C (0.787 g). The mixture was reacted overnight at room temperature with a flow of hydrogen. After completion of the reaction, the solvent was evaporated. After recrystallization with ethyl acetate/petroleum ether, the product 19a (5.9 g) was obtained as a yellow solid, with a yield of 83.4%.
Reaction SMILES: [CH2:1]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li]CCCC.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19]>C1COCC1>[CH2:1]([C:7]1[S:8][C:9]([Sn:18]([CH3:20])([CH3:19])[CH3:17])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1ccc([Sn](C)(C)C)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Hexylthiophene (23.0 g, 0.137 mol) was dissolved in 250 ml THF and n-BuLi (94 ml, 1.6 M in hexanes, 0.150 mol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 h and then cooled down to −78° C. A solution of trimethyltin chloride (32.8 g, 0.164 mol) in 100 ml THF was added dropwise. The mixture was allowed to warm slowly to room temperature and stirred for 2 h. After quenching with ice water and aqueous work-up, the product was distilled at 108° C. under high vacuum. 5-Hexyl-2-trimethylstannylthiophene was obtained as a colourless liquid (40.8 g, 90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].O1CC[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH:11]=[CH2:12]
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1Br
Product: C=CC(O)c1ccccc1Br

Procedure:
To 2-bromobenzaldehyde (27 g; 0.146 mmol.) in dry tetrahydrofuran cooled to -78° C. in a dry ice/isopropyl alcohol bath was added 175 ml of a 1.0M solution of vinyl Grignard reagent in tetrahydrofuran dropwise and the reaction allowed to slowly warm overnight to room temperature. The reaction mixture was quenched with saturated NH4Cl and the tetrahydrofuran was concentrated off. The reaction mixture was poured into water and extracted twice with diethylether, washed with water and then brine and dried over K2CO3 to afford the subtitle compound.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][C:34]=1[F:35])[C:16]([NH:18][C:19](=S)[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:17].[NH2:36][C:37]1[CH:38]=[C:39]([OH:43])[CH:40]=[N:41][CH:42]=1.CN(C)C=O>C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][C:34]=1[F:35])[C:16](/[N:18]=[C:19](\[NH:36][C:37]1[CH:42]=[N:41][CH:40]=[C:39]([OH:43])[CH:38]=1)/[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:17]
Reactant: Nc1cncc(O)c1
Reactant: O=C(NC(=S)Nc1cccc(C(F)(F)F)c1)c1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(/N=C(\Nc1cncc(O)c1)Nc1cccc(C(F)(F)F)c1)c1ccc(F)c(F)c1
Temperature: 65 °C

Procedure:
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (43 mg, 0.278 mmol), 3,4-difluoro-N-((3-(trifluoromethyl)phenyl)carbamothioyl)benzamide (100 mg, 0.278 mmol) and 5-aminopyridin-3-ol (31 mg, 0.278 mmol) and were combined in a glass vial and dry dimethylformamide (1.5 mL) was added. The vial was capped and the mixture was heated at 65° C. for 2 h. After cooling the mixture to room temperature, the mixture was diluted with ethyl acetate and washed with water then brine. The organic layer was evaporated onto silica gel and the product was purified by chromatography eluting with 50-100% ethyl acetate in hexanes to give (Z)-3,4-difluoro-N-(((5-hydroxypyridin-3-yl)amino)((3 (trifluoromethyl)phenyl)amino)methylene)benzamide as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F-].[Cs+].O.[CH3:12][C:13]1[N:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([C:16]2[CH:15]=[N:14][C:13]([CH3:12])=[N:18][CH:17]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: Cc1ncc(-c2cc(Cl)ncn2)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
As shown in step 9-i of Scheme 9, to 4,6-dichloropyrimidine (265.3 g, 1.781 mol) in 1.68 L DME was added CsF (241.5 g, 1.59 mol) and 700 mL water. The mixture was flushed with nitrogen gas for 30 minutes and Pd(PPh3)4 (22.05 g 19.08 mmol) was added. The resulting light yellow solution was flushed with nitrogen gas for an additional 40 minutes, heated to reflux, and a nitrogen-flushed solution of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (140 g, 636.1 mmol in 420 mL DME) was added dropwise over 1.6 hours. The resulting dark red solution was refluxed under an atmosphere of nitrogen for 16 hours. After this time the mixture was cooled to RT and 300 mL of water was added. The mixture was then cooled to 5° C. and stirred for 40 minutes. The resulting precipitate (6-chloro-2′-methyl-4,5′-bipyrimidine, compound 2039) was collected by filtration, washed with 50 mL water, followed by washing with 150 mL EtOAc. The filtrate was separated into two layers and the aqueous layer extracted with EtOAc (2×1 L). The combined organics were dried over Na2SO4, concentrated under reduced pressure, diluted with 300 mL of DCM, and purified by medium pressure silica gel chromatography (0-100% EtOAc/DCM). Fractions containing pure product were concentrated under reduced pressure and the concentrate treated with 400 mL of hexanes to produce compound 2039 as a solid. This material was combined with the solid product previously collected and treated with 400 mL of 1:1 THF/DCM. The resulting suspension was heated and transferred to a filtration funnel containing a plug of Florisil®. The plug was washed with additional 1:1 THF/DCM to dissolve any remaining solid material and then washed with 4:1 EtOAc/DCM (2×1 L). The combined filtrates were concentrated under reduced pressure to produce a pink solid which was triturated with 500 mL hexanes, collected by filtration, and dried under reduced pressure to provide 6-chloro-2′-methyl-4,5′-bipyrimidine (compound 2039, 88.8 g, 68% yield): LC-MS=207.01 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 2H), 9.10 (d, J=1.2 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 2.85 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[C:12]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:13]3[N:19]=[CH:18][N:17]=[C:16]([N:20]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:22][CH2:23][NH2:24])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)[CH3:3].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[C:12]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:13]3[N:19]=[CH:18][N:17]=[C:16]([N:20]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:22][CH2:23][NH:24][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:14]=3[N:15]=2)[CH2:8][CH2:9]1)[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)C1CCN(c2nc(N3CCOCC3)c3ncnc(N(CCCN)Cc4ccccc4)c3n2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C1CCN(c2nc(N3CCOCC3)c3ncnc(N(CCCNC(=O)c4ccccc4)Cc4ccccc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.75 g of 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-benzyl-N-(3-aminopropyl)-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine are dissolved in 8 ml of methylene chloride and mixed with 0.24 g of benzoyl chloride and 0.3 g of triethylamine in 2 ml of methylene chloride. The reaction mixture is stirred for 12 hours at ambient temperature and then extracted three times with water. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation. The residue is chromatographed over a silica gel column using methylene chloride/methanol=7:3. Yield: 0.7 g (77% of theory) Oil C34H43N9O2 (609.78)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=O.[OH2:20]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[C:2]([OH:20])([C:1]#[CH:6])[CH3:3]
Reactant: O
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Solvent: CS(C)=O
Product: C#CC(C)(O)c1ccccc1-c1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 46.6 g of p-phenylacetophenone in 250 ml. of dimethyl sulfoxide, there is added 65.5 g of lithium acetylide - ethylene diamine complex. After 18 hours at room temperature, the mixture is poured on 2 liters of iced water. The initial oil solidifies on standing, is filtered off and recrystallized from 150 mlof isopropyl alcohol to give 2-(p-biphenylyl)-3-butyn-2-ol, mp 75°-80° C.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.Cl.[C:29]1([NH:39]N)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[NH:39]1[C:29]2[C:30](=[CH:31][CH:32]=[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]3=2)[C:6]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[CH:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS 454.2 m/e: (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:29])[CH3:28])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.3 mmol), acetic anhydride (0.40 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmol) and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.55 g (99%) of N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC) 243-245° C. Anal. Calc'd. for C18H15F3N4O3S: C, 50.94; H, 3.56; N, 13.20; S, 7.56. Found: C, 50.64; H, 3.43; N, 12.64; S, 7.37.