Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.[OH:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O.NC1C=CC=CC=1>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][CH:29]([C:28]3[CH:27]=[C:26]([OH:25])[CH:33]=[CH:32][CH:31]=3)[CH:21]3[CH2:22][CH2:23][CH2:24][O:19][CH:20]3[C:10]=2[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: C1=COCCC1
Reactant: O=Cc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Nc1ccccc1
Solvent: CC#N
Product: CC(C)(C)c1ccc2c(c1)C1OCCCC1C(c1cccc(O)c1)N2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
99.0 g (663 mmol) of 4-tert-butylaniline was dissolved in 500 ml of acetonitrile, and 51.6 ml (670 mmol) of trifluoroacetic acid was added with ice-cooling. 46.4 g (670 mmol) of 3,4-dihydro-2H-pyran and 81.8 g (670 mmol) of 3-hydroxybenzaldehyde in 500 ml of acetonitrile were initially introduced in a second flask with ice-cooling. The aniline*|trifluoroacetic acid salt pre-cooled to 50° C. was added rapidly to this reaction solution, and stirring was continued at this temperature for about 2 h. The reaction mixture was evaporated, and the residue was suspended in 2 l of water and adjusted to pH 12 using sodium hydroxide solution. The emulsion formed was extracted 2× with 1 l of tert-butyl methyl ether. The org. phase was dried over Na2SO4 and crystallised overnight in at 4° C. Precipitated colourless product 1 was filtered off and dried, giving 6.00 of colourless crystals. 3-(9-tert-Butyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-5-yl)phenol was isolated from the filtrate as described under DE10360154.6 and could also be converted into comp. 1 as described under c.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:21]=[N:22][C:23]([C:26]3[C:27](C)=[N:28][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:30]=3)=[CH:24][CH:25]=2)=[CH:9][N:10](C)[CH:11](C2C=CC=CC=2)C)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:11][NH:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C(=CN(C)C(C)c2ccccc2)c2ccc(Cl)cc2)cn1
Agent: [Pd]
Solvent: CCO
Product: CNCC(c1ccccc1)c1ccc(-c2cn[nH]c2)nc1

Procedure:
To a solution of {2-(4-Chloro-phenyl)-2-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-vinyl}-methyl-(1-phenyl-ethyl)-amine in ethanol was added palladium, 10 wt. % on activated carbon and the reaction mixture was subjected to a hydrogen atmosphere for 17 hours. The mixture was filtered through Celite®, the mother liquor was concentrated, the residue was purified by column chromatography (SiO2), eluting with dichloromethane: methanol: acetic acid:water (240:20:3:2) to dichloromethane: methanol: acetic acid:water (90:18:3:2) to afford the title compound. LC/MS: (PS-A2) Rt 1.59 [M+H]+ 293.18. 1H NMR (Me-d3-OD) δ 2.35 (3H, s), 2.40 (3H, s), 3.25 (2H, s), 4.15-4.20 (1H, t), 7.10-7.18 (1H, m), 7.25 (4H, m), 7.45 (1H, d), 7.67 (1H, dd), 7.80 (1H, s), 8.38 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[N:6]=1.N[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH2:15][NH:1][C:2]2[O:3][CH:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[O:7])[N:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1=NC(=O)C(c2ccccc2)O1
Reactant: NCC1CCCCC1
Product: O=C1N=C(NCC2CCCCC2)OC1c1ccccc1

Procedure:
Synthesis was performed from 2-amino-5-phenyl-1,3-oxazol-4(5H)-one and aminomethylcyclohexane according to Method G+H.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCCN(Cc3ccc(F)cc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCCN(Cc5ccc(F)cc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-4-(4-(4-fluorobenzyl)-1,4-diazepan-1-yl)-3-nitropyridin-2-amine (0.047 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 4.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 0 to 5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid (0.020 g, 35%); 1H-NMR (500 MHz, DMSO-d6) 2.00 (m, 2H), 2.75-2.85 (m, 4H) and 3.86 (m, 4H) (homopiperazine protons), 2.99 (s, 6H, N(CH3)2), 3.66 (s, 2H, N—CH2), 6.82 (d, J=9.00 Hz, 2H) and 8.00 (d, J=8.84 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.14 (t, J=8.93 Hz, 2H) and 7.39 (dd, J=8.13, 5.42 Hz, 2H) (3,5-ArH and 2,6-ArH), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.08 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:11][CH2:12][CH3:13])[NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C([O-])(=O)C.[Na+].CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1>C(O)(=O)C>[CH2:11]([C:4]1[NH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([N:1]2[CH:21]=[CH:25][CH:24]=[CH:23]2)[N:3]=1)[CH2:12][CH3:13]
Reactant: CCCc1nc(N)c(C(=O)OC)[nH]1
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(-n2cccc2)c(C(=O)OC)[nH]1
Yield: 46.2 %

Procedure:
To stirred acetic acid (1.5 L) at 80° C. was added over a 5-minute period a mixture of methyl -4-amino-2-propylimidazol-5-carboxylate (Example 4, 145 g, 0.798 mol) and sodium acetate (388 g, 4.73 mol). The mixture was heated at reflux for 5 minutes and then 2,5-dimethoxy-tetrahydrofuran (117 g, 0.885 mol) added all at once. The resulting dark solution was refluxed for 20 minutes, then poured onto ice. The gummy mixture was extracted with dichloromethane, the combined organic layers washed with water and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue dissolved in dichloromethane (2 L). The dichloromethane solution was treated with silica gel (500 g) and the suspension filtered through a bed of silica gel (300 g) eluting with dichloromethane. The filtrate was evaporated to dryness under reduced pressure and the crude product recrystallized from ether/hexane (2:1) to provide 86 g (46% yield) methyl 2-propyl-4-(1 H-pyrrol-1-yl)imidazol-5-carboxylate, mp 135°-138° C. MS (DEI) 234 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][NH:25][C:26](=[O:35])[CH2:27][NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:27][C:26]([NH:25][CH3:24])=[O:35])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:10][CH2:11]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CNC(=O)CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CNC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 45.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (9.45 g) and N-methyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinamide (6.26 g) in 2-propanol (80 mL) was added piperidinium acetate (4.05 g). The reaction mixture was stirred at 80° C. for 3.5 hr and concentrated. Water and THF were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate/heptane to give the title compound (6.50 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[C@@H:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Li]>C(OCC)C>[C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:15])[CH3:26]
Reactant: [Li]C
Reactant: COc1ccc(C[C@H]2[C@@H](C(=O)O)CCCN2Cc2ccccc2)cc1
Solvent: CCOCC
Product: COc1ccc(C[C@H]2[C@@H](C(C)=O)CCCN2Cc2ccccc2)cc1

Procedure:
A solution of 33.9 g. of cis-1-benzyl-2-(p-methoxybenzyl)-3-piperidinecarboxylic acid in 340 ml. of diethyl ether is stirred at room temperature while 200 ml. of 1M methyl lithium is added dropwise. After this addition is completed, the reaction mixture is stirred and refluxed for 4 hours and poured over ice. The ether layer is separated and washed with 100 ml. of saturated aqueous sodium bicarbonate solution, dried, and filtered. The filtrate is concentrated to yield cis-3-acetyl-1-benzyl-2-(p-methoxybenzyl)piperidine.
Reaction SMILES: [H-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][OH:12].[CH2:13]([Sn:17]([CH2:26]I)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O1CCCC1.CCOCC>[CH2:13]([Sn:17]([CH2:26][O:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH3:16]
Reactant: OCCCc1ccccn1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)COCCCc1ccccn1
Reaction time: 0.5 h

Procedure:
Potassium hydride (52 mg, 1.30 mmol) was added to a solution of 3-(2-pyridyl)propan-1-ol (161.8 mg, 1.18 mmol) in tetrahydrofuran (3 ml) at room temperature under argon. After 30 minutes, a solution of tributylstannylmethyl iodide (510 mg, 1.18 mmol) in tetrahydrofuran (0.5 ml) was added. After stirring was continued at room temperature for 9 days, the mixture was diluted with ether and washed thoroughly with water. Evaporation of the dried (magnesium sulphate) organic layer gave an oil, which was flash chromatographed on silica using 60% ethyl ether/hexane. Fractions with Rf of about 0.53 on evaporation gave the title ether as a bright yellow oil.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[CH2:12]([O:19][CH2:20][CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23](O)=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[CH2:12]([O:19][CH2:20][CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([NH:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9])=[O:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: COC(=O)c1c(Br)ccn1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(Br)ccn1NC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 102.7 %

Procedure:
Methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (2.83 g, 12.92 mmol) was treated with (S)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)butanoic acid (4 g, 12.93 mmol), N,N-diisopropylethylamine (7.4 mL, 42.6 mmol) and T3P® (50% in ethyl acetate, 10.8 mL, 18.14 mmol) according to the method of Preparation 5a to give 6.77 g (84% yield) of the desired compound. Purity 81%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[CH3:24][O:23][N:22]([CH3:21])[C:17]([CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1)=[O:19]
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Yield: 87.1 %

Procedure:
1-[(Benzyloxy)carbonyl]piperidine-3-carboxylic acid (5.86 g, 22.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.55 g, 36.4 mmol) in tetrahydrofuran (60 mL) was stirred with triethylamine (5.50 mL, 39.5 mmol), 1-hydroxybenzotriazole (1.17 g, 8.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.18 g, 37.4 mmol) at room temperature for one day. After addition of water, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a colorless oil (5.95 g, yield 87%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.[CH2:20]([O:27][C:28](=[O:41])[CH2:29][CH2:30][NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28](=[O:41])[CH2:29][CH2:30][NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:34]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CC(=O)Nc2cccc(C(=O)NCCC(=O)OCc3ccccc3)c2)cc1

Procedure:
p-Cyanophenylacetic acid and N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate are coupled to give N-[m-[2-(p-cyanophenyl)acetamido]benzoyl]-β-alanine benzyl ester, m.p. 98°-99° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 95.5 %

Procedure:
To 2.0 g (14.5 mmol) of 3-nitroaniline and 4.5 ml (32 mmol) of triethylamine in 60 ml of methylene chloride stirred at room temperature was added 5.4 ml (16 mmol) of octadecanoyl chloride in 10 ml of methylene chloride. The reaction mixture was kept at room temperature for 18 hours and then was washed with 1N HCl, dried and concentrated at reduced pressure to a solid. Recrystallization from methanol gave 5.6 g (95% yield, mp 75°-76°) of N-(3-nitrophenyl)octadecanamide.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18]([Mg]Br)[CH2:19][CH:20]=[CH2:21]>C1COCC1.CCOCC>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH2:21][CH2:20][CH:19]=[CH2:18])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C=CCC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (595 mg) in THF (3 mL) at −78° C. was added 3-butenyl magnesium bromide (7.8 mL of 0.5 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 4 hr. The reaction was quenched with H2O and 1N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of Et2O and triturated with hexanes to yield the title compound as a tan solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[CH:10]=[CH:9][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1c(Br)cnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(Br)cnc21
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (0.50 g, 2.160 mmol) was placed in DMF (5 mL) at 0° C. NaH (0.10 g, 2.59 mmol) was then added, and the reaction was stirred for 20 minutes. Benzenesulfonyl chloride (0.304 mL, 2.38 mmol) was then added, and the reaction was stirred for 30 minutes at 0° C. Water (50 mL) was then added. The precipitate was filtered, washed with water, washed with ether, and dried to give 5-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.8 g, 99.6% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][O:48]S(C)(=O)=O)[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:53][NH:54][CH3:55].C1C[O:59]CC1>>[CH:47]([OH:48])=[O:59].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][N:54]([CH3:55])[CH3:53])[CH:44]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C1CCOC1
Reactant: CNC
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCOS(C)(=O)=O)c2)n1
Product: CN(C)CCCn1cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)cn1
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
To a solution of Intermediate 113f (0.125 mmol) in THF (1.5 mL) was added dimethylamine (2M in MeOH, 0.5 mL, 1.0 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, followed by MDAP (Method 7) purification, to give the title compound (10 mg, 12%). LCMS (Method 5): Rt 3.36 min, m/z 680 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.21 (9H, s), 1.54-1.65 (2H, m), 1.67-1.77 (4H, m), 1.81-1.95 (4H, m), 1.99-2.07 (4H, m) 2.08 (6H, s), 2.16 (2H, t, J=6.9 Hz), 3.10 (4H, t, J=5.2 Hz), 4.09 (2H, t, J=7.1 Hz), 4.79 (1H, td, J=8.4, 5.5 Hz), 5.51 (1H, t, J=4.5 Hz), 6.21 (1H, s), 7.09-7.14 (2H, m), 7.22-7.37 (4H, m), 7.55-7.62 (3H, m), 7.97-8.01 (2H, m), 8.22 (0.4H, br s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][O:16][C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)=[O:18]>Cl>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:26][CH:25]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC2CNCCN2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of N-methyl piperazine (80 g, 0.91 mol) and triethylamine (232 g, 2.29 mol) in absolute alcohol (1750 ml) was added dropwise at 0° C. a solution of 4-methoxycarbonyl-benzyl bromide (252 g, 1.1034 mol) in absolute alcohol (250 ml). The mixture was stirred overnight at RT. Then the mixture was concentrated and the residue obtained was taken up in 1.5N HCl (3 L) then washed with diethyl ether (3 times) and ethyl acetate. The solution was neutralized with a 10% aqueous NaOH solution and basified up to pH=8 with a 10% aqueous NaHCO3 solution. The product was extracted with CHCl3, washed with water and brine then dried over Na2SO4. The solvent was removed and the crude was purified by column chromatography CHCl3/MeOH to give N-methyl(4-methoxy carbonyl benzyl)piperazine (150 g, 70%) as a brown liquid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:50])([CH3:49])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1>O.C(OCC)(=O)C>[OH:13][C:14]([CH3:49])([CH3:50])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OCC(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.91 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.69 g, 68%).
Reaction SMILES: [S:1]1(=[O:9])(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH:14]=O.[NH2:20][C:21]([CH3:26])=[CH:22][C:23](=[O:25])[CH3:24]>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]2[C:22]([C:23](=[O:25])[CH3:24])=[C:21]([CH3:26])[NH:20][C:3]3[CH2:4][CH2:5][CH2:6][S:1](=[O:9])(=[O:8])[C:2]2=3)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCCS(=O)(=O)C1
Reactant: CC(=O)C=C(C)N
Solvent: CCO
Product: CC(=O)C1=C(C)NC2=C(C1c1ccc(Cl)c(Cl)c1)S(=O)(=O)CCC2

Procedure:
A solution of tetrahydrothiopyran-3-one-1,1-dioxide (255 mg, 1.72 mmol), 3,4-dichlorobenzaldehyde (250 mg, 1.43 mmol) and 4-amino-3-penten-2-one (140 mg, 1.41 mmol) in ethanol (5 mL) was heated to reflux for 24 hours and cooled. The solid that precipitated was collected, washed with ethanol, and dried to provide the title compound.