Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)CCC.[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH3:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:24]([CH2:27][CH3:28])([O-:26])=[O:25]>C(O)(=O)C>[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:27]([N+:24]([O-:26])=[O:25])[CH3:28])=[CH:16][C:15]=1[O:22][CH3:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: CC[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCCCN
Product: COc1cc(C=C(C)[N+](=O)[O-])ccc1OCc1ccccc1
Yield: 18 %

Procedure:
4.02 g (55.0 mmol) of butylamine was added dropwise to a mixture of 12.1 g (50.0 mmol) of 4-benzyloxy-3-methoxybenzaldehyde, 5.63 g (75.0 mmol) of nitroethane and 120 ml of acetic acid and refluxed for 5 hours by heating. The reaction mixture was cooled and extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:1) to give 2.70 g of 1-benzyloxy-2-methoxy-4-(2-nitropropenyl)benzene.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[O:4][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30])([CH3:23])[CH3:22].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:20])[C:2]=1[S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1
Reactant: CC(C)c1ccccc1S
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(Sc2ccccc2C(C)C)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (prepared in example CCC), 2.2 mmol of 2-isopropylbenzenethiol, and 2.2 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 64°-66° C.). 1H NMR (DMSO-d6) δ 0.80 (m, 6 H), 0.95 (m, 1 H), 1.17 (t, 7 H), 1.42 (m, 1 H), 1.93 (m, 2 H), 3.20 (m, 1 H), 3.45 (2 H+H2O), 5.84 (d, 1 H), 6.55 (t, 1 H), 6.93 (t, 1 H), 7.12 (d, 1 H), 7.40 (m, 5 H).
Reaction SMILES: CN1CCOCC1.Cl[S:9]([C:12]1[CH:17]=[CH:16][N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](=[O:24])[C:13]=1[N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)(=[O:11])=[O:10].Cl.[CH:41]1([CH2:45][NH2:46])[CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[NH2:25][C:13]1[C:14](=[O:24])[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:17][C:12]=1[S:9](=[O:10])(=[O:11])[NH:46][CH2:45][CH:41]1[CH2:44][CH2:43][CH2:42]1
Reactant: NCC1CCC1
Reactant: CCOC(=O)Cn1ccc(S(=O)(=O)Cl)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1=O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc(S(=O)(=O)NCC2CCC2)c(N)c1=O
Temperature: 25 °C

Procedure:
NMM (1.43 mL, 13.0 mmol) was added to a stirred mixture of 4-chlorosulfonyl-3-(N,N-di-t-butoxycarbonylamino)-1-ethyloxycarbonylmethyl-2-pyridinone (as a mixture from Step H, 0.84 g) and cyclobutylmethylamine hydrochloride (348 mg, 2.86 mmol) in methylene chloride (15 mL). After 16 h the reaction was diluted with methylene chloride and washed with 10% citric acid solution. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica (40% ethyl acetate/hexanes). HCl gas was bubbled through a stirred solution of the resulting compound in ethyl acetate (10 mL) at 0° C. for 15 min. The reaction was warmed to rt and after a further 3 h it was evaporated to give the title compound as a solid;
Reaction SMILES: O=[C:2]([N:12]([CH3:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C@@H:3]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]1[OH:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:11][CH2:10][C@@H:8]1[C@@H:6]([OH:7])[C@@H:4]([OH:5])[CH:3]([CH2:2][N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:21])[O:9]1
Reactant: COc1ccc(N(C)C(=O)[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N(C)CC2O[C@H](CO)[C@@H](O)[C@H]2O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
N-(2,5-anhydro-D-allonoyl)-4-methoxy-N-methyl-aniline (0.7 g, 2.4 mmol) was dissolved in anhydrous THF (80 mL) and the solution was cooled to 0° C. After 10 minutes, a lithium aluminium hydride solution (9.6 mL, 1M) in THF was added slowly over a period of 5 to 7 minutes and the resulting mixture was stirred for 1 hour. The reaction temperature was raised slowly from 0° C. to room temperature and stirring was continued for an additional 2 hours. The progress of the reaction was monitored by HPLC and the reaction was quenched carefully with water (300 mL) and adjusted to pH 7.5 with 1M HCl. The solids were separated by centrifugation and the residue was washed with water (2×50 mL). The combined solutions were evaporated in vacuo and the residue was treated with methanol (100 mL). The remaining solid was again separated by filtration and the filtrate was evaporated to dryness. The residue was purified by RP HPLC and evaporation of the appropriate fractions yielded the title compound as a yellow oil (170 mg, 0.6 mmol, 25%): MS (ES) m/z 284 [M+H]+, 306 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[O:11][CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: COc1cc(Br)c(O)cc1F
Reactant: BrCC1CC1
Product: COc1cc(Br)c(OCC2CC2)cc1F

Procedure:
Starting from 2-bromo-5-fluoro-4-methoxy-phenol (example B.a1) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([C:10]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][CH:11]2[CH2:13]Cl)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C>C(O)C>[CH3:1][N:2]([CH2:13][CH:11]1[CH2:12][C:10]1([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:3]
Reactant: CNC
Reactant: ClCC1CC1(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)CC1CC1(c1ccccc1)c1ccccc1
Reaction time: 32 h

Procedure:
To a solution of 40% aqueous dimethylamine (10 ml) in ethanol (10 ml) was added a solution of 2,2-diphenylcyclopropylmethyl chloride (0.50 g) in ethanol (10 ml) and triethylamine (1.0 g) at room temperature, and stirring was carried out at 35°-40° C for 32 hours. The reaction mixture was evaporated and poured into a 10% aqueous sodium hydroxide solution. The etheral extract was dried and chromatographed to afford N,N-dimethyl-2,2-diphenylcyclopropylmethylamine as an oily substance. M.P. 231°-233° C (hydrochloride).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[H-].[Na+].[Cl:16][CH2:17][CH2:18][CH2:19]Cl>CN(C=O)C>[CH2:1]([N:3]([CH2:19][CH2:18][CH2:17][Cl:16])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(C)cc1
Reactant: ClCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCCl)S(=O)(=O)c1ccc(C)cc1
Temperature: 53 °C
Yield: 42 %

Procedure:
To N-ethyl-p-toluenesulfonamide (5.01 g, 0.0251 mol) in DMF (50 mL) in a dry flask is added sodium hydride (80% in oil, 0.93 g, 0.031 mol). After gas evolution subsides, 1,3-dichloropropane (22.48 g, 0.199 mol) is added. The mixture is heated at 53° C. for 10 h then cooled and poured into ice water (300 mL), which is extracted twice with ether. The combined extracts are washed with 1% sodium bisulfite, water (3×), and brine. Removal of solvent by rotary evaporation then Kugelrohr distillation gives crude product, which is chromatographed on silica gel (30% hexane/CHCl3) to furnish 2.91 g product (42%) NMR (CDCl3) δ 1.15 (t, 3H), 1.9-2.2 (m, 2H), 2.44 (s, 3H), 3.11-3.35 (m, 4H), 3.6 (t, 2H), 7.3 (d, 2H), 7.74 (d, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[F:12])=O.[NH2:13][C:14]([NH2:16])=[O:15].[OH-].[Na+]>CC#N>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]([NH2:16])[O:15][CH:2]=2)=[C:6]([F:12])[CH:7]=1
Reactant: NC(N)=O
Reactant: O=C(CBr)c1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1nc(-c2ccc(Br)cc2F)co1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 2-bromo-1-(4-bromo-2-fluorophenyl)ethanone (53 mg, 0.18 mmol) and urea (10.6 mg, 0.18 mmol) in CH3CN (0.7 mL) was heated at 80° Celsius for 18 hours. The mixture was cooled to rt and made basic with NaOH (2 N). The resulting solution was extracted with EtOAc and the extract was dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified using FCC to give 4-(4-bromo-2-fluorophenyl)oxazol-2-amine (37 mg, 82%). MS (ESI): mass calcd. for C9H6BrFN2O, 255.96; m/z found, 257.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.78 (m, 1H), 7.58 (d, J=4.3, 1H), 7.36-7.32 (m, 1H), 7.28 (dd, J=10.5, 1.9, 1H), 4.60 (s, 2H).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.Cl[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]2[O:11][CH:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)CCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1OC1c1ccc(OC)cc1
Temperature: 24 °C
Reaction time: 16 h

Procedure:
Ethanol free sodium ethoxide was mixed with 200 ml. of toluene and cooled to 0°C. A solution of p-methoxybenzaldehyde, 56.0 g. (0.412 mole), and ethyl chloroacetate, 50.5 g. (0.412 mole), in 200 ml. of toluene was added at such a rate that the temperature remained below 10°C. After stirring at 24°C. for 16 hours, the mixture was washed twice with 400 ml. portions of water and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow liquid of about 80% purity (81.2 g.). The liquid solidified on standing at 5°C. and was further purified by washing with a small volume of cold ethanol to give pale yellow crystals of ethyl 3-(4-methoxyphenyl)-2,3-epoxypropionate having a melting point of between 40° and 43°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([Cl:18])[C:3]=1[N:19]1[C:23]([NH2:24])=[CH:22][C:21]([C:25]#[N:26])=[N:20]1.[Br:27]N1C(=O)CCC1=O>C(#N)C>[Cl:18][C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:12][CH:13]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[N:19]1[C:23]([NH2:24])=[C:22]([Br:27])[C:21]([C:25]#[N:26])=[N:20]1
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)c(N)c1Br
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
A mixture of 1-[2,6-dichloro-4-(4-trifluoromethylphenyl)phenyl]-3-cyano-5-aminopyrazole (1 g), N-bromosuccinimide (0.5 g) and acetonitrile was stirred at 20° C. for 90 minutes, then concentrated and the residue was mixed with diethyl ether, washed with saturated aqueous NaHCO3 solution, dried, filtered and the filtrate concentrated and purified via chromatography. The desired product as a solid (1.04 g, mp 178-180° C.) was obtained.
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:31][C:32]([N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:42][C:41]3=[O:50])[CH2:36][CH2:35]2)=[O:33])[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[N:25]1([CH:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH:16]([NH:31][C:32]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:49][C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[NH:42][C:41]4=[O:50])[CH2:38][CH2:39]3)=[O:33])[CH2:15][C:12]3[CH:11]=[CH:10][C:9](=[O:8])[NH:14][CH:13]=3)[CH2:24][CH2:23]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(NC(Cc1ccc(OCc2ccccc2)nc1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(NC(Cc1ccc(=O)[nH]c1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reaction time: 8 h

Procedure:
A flask was charged with 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(6-benzyloxy-pyridin-3-ylmethyl)-2-[1,4′]bipiperidinyl-1′-yl-2-oxo-ethyl]-amide (27 mg, 0.04 mmol), palladium on charcoal (10%, 4 mg), and methanol (1 mL). The flask was flushed with nitrogen, then hydrogen, and allowed to stir under an atmosphere of hydrogen overnight. The flask was flushed with nitrogen, and the reaction filtered through celite to give 22.1 mg (94%). LC/MS: tR=0.93 min, 590.32 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=1.O>C1(C)C=CC=CC=1>[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 38.7 %

Procedure:
3.98 g (0.02 mol) of 1-benzyl-4-hydroxy-piperidine in 70 ml of toluene were treated with 0.624 g of NaH (50%) and heated at reflux for 1 1/2 hr. while gassing with argon. Subsequently, 3.32 g (0.022 mol) of methyl 4-amino-benzoate dissolved in 80 ml of toluene were added dropwise over 1/2 hr. and the mixture was heated at reflux for a further 2 hrs. The suspension obtained was added to 400 mi of water and the mixture was stirred. The precipitate was filtered off under suction and washed with toluene and hexane. The organic phase of the filtrate was separated, washed three times with water, dried over MgSO4 and evaporated and the residue was combined with the filter material. Chromatography was carried out over silica gel with chloroform as the eluent and recrystallization was carried out from ethyl acetate/hexane. 2.4 g (38.7%) of 1-benzyl-piperidin-4-yl 4-amino-benzoate were obtained as colorless crystals; m.p. 119°-120° C.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:18][C:17]=1[CH3:26])=[N:5]/[O:6][CH3:7].COC(=O)/[C:31](/C1C=CC=CC=1COC1C=CC(C=C(Cl)Cl)=CC=1Cl)=[N:32]/OC>>[Cl:24][C:23]([Cl:25])=[CH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2/[C:4](=[N:5]\[O:6][CH3:7])/[C:3]([NH:32][CH3:31])=[O:2])=[C:17]([CH3:26])[CH:18]=1
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1ccc(C=C(Cl)Cl)cc1Cl
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1ccc(C=C(Cl)Cl)cc1C
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc(C=C(Cl)Cl)cc1C
Yield: 86 %

Procedure:
The procedure of Example 40 was repeated except for using methyl-(E)-2-(2-((4-(2,2-dichlorovinyl)-2-methylphenoxy)methyl)phenyl)-2-methoxyiminoacetate (0.408 g, 1 mmol) obtained in Example 41 instead methyl-(E)-2-(2-((2-chloro-4-(2,2-dichlorovinyl)phenoxy)methyl)phenyl)-2-methoxyiminoacetate to obtain the title compound (0.350 g, 86%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[S:20][C:21]([C:24]([NH2:26])=[O:25])=[CH:22][N:23]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[S:20][C:21]([C:24]([NH2:26])=[O:25])=[CH:22][N:23]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: NC(=O)c1cnc(Br)s1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(N)=O)s3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 2-bromo-1,3-thiazole-5-carboxamide (J. Am. Chem. Soc. 1952, 74, 5799).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.CN([CH:17]=[O:18])C.[Cl-].[NH4+]>C(OCC)C.O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[CH:17]=[O:18]
Reactant: Brc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: O=Cc1cncc(Br)c1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
In diethyl ether (42.0 mL) was dissolved 3,5-dibromopyridine (1.00 g, 4.22 mmol). n-Butyllithium (2.76 mol/L solution in n-hexane, 1.61 mL, 4.43 mmol) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Further, DMF (0.98 mL, 12.7 mmol) was added and the mixture was stirred for 3 hours allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 5-bromonicotinaldehyde (314 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.[Br:44][C:45]1[CH:46]=[N:47][C:48](I)=[N:49][CH:50]=1>>[Br:44][C:45]1[CH:46]=[N:47][C:48]([C:11]2[CH:10]=[CH:9][C:8]([C:7]3[N:6]=[C:5]4[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:24]([O:26][C@H:27]5[C@H:31]6[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]6[O:29][CH2:28]5)=[N:25][C:4]4=[CH:3][C:2]=3[Cl:1])=[CH:13][CH:12]=2)=[N:49][CH:50]=1
Reactant: Brc1cnc(I)nc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ncc(Br)cn4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 5-bromo-2-iodopyrimidine following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.28 min; Mass spectrum (ESI+): m/z=660, 662 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: C1CC(N2CCOCC2)CN1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CCOCC4)C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4-(pyrrolidin-3-yl)morpholine via General Procedure E to give 26.9 mg of 287 following reverse phase purification. MS (Q1) 518.2 (M)+
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32](OC)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=2)(=[O:38])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1.O>CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32]([C:2]5[S:3][CH:4]=[CH:5][N:6]=5)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:46])[F:47])[CH:40]=2)(=[O:38])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1
Reactant: Brc1nccs1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cccc(C(F)(F)F)c1)C2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cccc(C(F)(F)F)c1)C2
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 57.8 %

Procedure:
2-Bromothiazole (187 mg, 1.139 mmol) in dry ether (2 mL) was added to butyllithium (1.6M in hexanes) (729 μl, 1.167 mmol) in dry ether (4 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. A solution of (R)-methyl 1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (200 mg, 0.373 mmol) in dry ether (4 mL) was added dropwise and the reaction mixture was stirred for 30 minutes at −78° C. Water (20 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried (magnesium sulfate), and solvent removed to give a yellow oil. The crude product was purified first by chromatography on silica gel (gradient: 0 to 40% isohexane in ethyl acetate) followed by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 40-65% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (127 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.73 min, m+H=589.0; 1H NMR (400 MHz, CDCl3): δ 8.04 (1H, d, J=3.1 Hz), 7.97 (1H, s), 7.90 (1H, d, J=7.9 Hz), 7.81 (1H, d, J=7.9 Hz), 7.70-7.59 (2H, m), 7.46-7.39 (2H, m), 7.30 (1H, s), 7.13-7.19 (2H, m), 6.53 (1H, d, J=2.2 Hz), 5.54 (1H, dd, J=12.4, 2.0 Hz), 4.21 (1H, d, J=16.8 Hz), 3.93-3.89 (1H, m), 2.95-2.84 (2H, m), 2.80 (1H, d, J=12.5 Hz), 2.61-2.52 (2H, m).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:29]=[C:30]([NH:34]N)[CH:31]=[CH:32][CH:33]=1>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:26]([F:25])([F:36])[F:37])[CH:29]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Reactant: NNc1cccc(OC(F)(F)F)c1
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1cccc(OC(F)(F)F)c1

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and 3-trifluoromethoxy-phenylhydrazine according to the method described for example 91. MS: M=465.2 (M+H)+