Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[Zn+].[CH:8]([N:11]([CH:33]([CH3:35])[CH3:34])[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([NH:23][C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])([CH3:10])[CH3:9]>O1CCCC1.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>[CH3:35][CH:33]([N:11]([CH:8]([CH3:10])[CH3:9])[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([NH:23][C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)=[CH:29][CH:30]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH3:34]
Reactant: [Zn+]c1cccs1
Reactant: COc1ccc(NC(=O)c2ccc(I)cc2)cc1OCCN(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2ccc(-c3cccs3)cc2)cc1OCCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-thienylzinc bromide in tetrahydrofuran (0.5M, 5 mL, 2.5 mmol) was added to a solution of N-[3-[2-(diisopropylamino)ethoxy]-4-methoxypheny]-4-iodobenzamide (WO 99/01127) (0.5 g, 1 mmol) in tetrahydrofuran (5 mL) containing tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.06 mmol), and the mixture was stirred at RT for 16 h. The reaction was quenched with saturated ammonium chloride and extracted with ether and dichloromethane. The organic phase was dried (MgSO4), concentrated in vacuo, and chromatographed (silica gel, 5% methanol/dichloromethane) to afford the title compound (0.1 g) MS(ES) m/e 452.8 [M+H]+.
Reaction SMILES: Br[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.[NH2:12][C:13]([NH2:15])=[O:14]>C(O)C>[CH2:5]([C:2]1[O:14][C:13]([NH2:15])=[N:12][CH:3]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CC(Br)Cc1ccccc1
Reactant: NC(N)=O
Solvent: CCO
Product: Nc1ncc(Cc2ccccc2)o1
Temperature: 90 °C

Procedure:
To a solution of 2-bromo-3-phenyl-propionaldehyde (26.0 g, purity 60%, 0.0732 mol) in ethanol (300 ml) was added urea (14.66 g, 0.244 mol) and the reaction mixture was heated to 90° C. for 12 h. The solvent was evaporated, the residue was diluted with dichloromethane and washed with aqueous sodium hydroxide solution (2 N) and water. The organic phase was extracted three times with aqueous hydrochloric acid solution (2 N). The combined aqueous phases were adjusted to pH 10 with aqueous sodium hydroxide solution (2 N) and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a yellow solid (1.78 g, 14%). MS ISP (m/e): 175.2 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH:15]2[NH:17][CH:11]([CH2:12][O:13][CH2:14]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]1[NH:31][C:30]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[N:29][C@@H:28]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[Cl:44])[C:27]=1[C:45]([O:47][CH3:48])=[O:46].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][CH:11]2[N:17]([CH2:25][C:26]3[NH:31][C:30]([C:32]4[S:33][CH:34]=[CH:35][N:36]=4)=[N:29][C@@H:28]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[Cl:44])[C:27]=3[C:45]([O:47][CH3:48])=[O:46])[CH:15]([CH2:14][O:13][CH2:12]2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: CCOC(=O)CC1(NC(=O)OC(C)(C)C)CC2COCC(C1)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1(NC(=O)OC(C)(C)C)CC2COCC(C1)N2CC1=C(C(=O)OC)[C@H](c2ccc(F)cc2Cl)N=C(c2nccs2)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-[7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate 146a (0.1 g, 0.3 mmol) and methyl (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate C (90 mg, 0.2 mmol), DIPEA (77.4 mg, 0.6 mmol) in DCM (5 mL) was stirred for 12 hours at room temperature. The mixture was concentrated to give crude methyl (4R)-6-[[7-(tert-butoxycarbonylamino)-7-(2-ethoxy-2-oxo-ethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 146b. MS: calc'd (MH+) 692, exp (MH+) 692.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[N+](C1C=CC=CC=1)([O-])=O>>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:14]1[C:13]1[CH:16]=[CH:17][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(O)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1ccc(-c2nc3ccccc3o2)cc1
Yield: 73 %

Procedure:
A mixture containing 5.45 g. (0.05 mole) of o-aminophenol and 6.10 g. (0.05 mole) of p-hydroxybenzaldehyde in 75 ml. of nitrobenzene was heated to reflux for 5 hr. On cooling to 30° a dark solid appears which was filtered, washed with hot toluene, and air-dried. Recrystallization from ethanol gave a 73% yield of 4-(2-benzoxazolyl)phenol (mp 255°-258°).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[Cl:11][C:12]1[C:13]([O:22][C:23]2[C:27]([CH2:28][CH3:29])=[C:26]([CH3:30])[NH:25][N:24]=2)=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:25]1[C:26]([CH3:30])=[C:27]([CH2:28][CH3:29])[C:23]([O:22][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:15][N:14]=2)=[N:24]1)=[O:10]
Reactant: CCc1c(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]c1C
Reactant: CN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1c(Oc2ncc(C(F)(F)F)cc2Cl)nn(C(=O)NC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Potassium carbonate (0.83 g, 6.0 mmol) and methyl isocyanate (0.29 g, 5.0 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4-ethyl-5-methylpyrazole (1.83 g, 6.0 mmol) in ethyl acetate (25 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4-ethyl-5-methylpyrazole-1-carboxamide (1.14 g, yield: 62.9%). mp: 84-86° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.04 (t, J=7.6 Hz, 3H), 2.26 (q, J=7.6 Hz, 2H), 2.59 (s, 3H), 2.93 (d, J=5.0 Hz, 3H), 6.80-7.05 (m, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.32 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([OH:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(O)c1cccc([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
26.4 g (160 mmol) of 1-(3-nitrophenyl)ethanone are suspended in 270 ml of methanol, and 6.1 g (160 mmol) of sodium borohydride are added in portions with ice cooling. The reaction mixture is subsequently stirred for a further 3 h without cooling, diluted with 300 ml of dichloromethane and washed with 3×200 ml of water. The organic phase is dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NCc1ccncc1)C(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A solution of N'-t-butyl-N'-benzoylhydrazine (0.5 g, 0.00026 mol) in 10 ml of toluene was treated with 50% sodium hydroxide (0.6 g) followed by isonicotinyl chloride hydrochloride (0.47 g, 0.0026 mol). The mixture was stirred at 23° C. overnight. The solids were removed by filtration and washed with water followed by ether to afford N'-t-butyl-N-isonicotinyl-N'-benzoylhydrazine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH2:5].S(=O)(=O)(O)[O-].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.CN1CCOCC1>CN(C=O)C>[C:20]([O:19][C:17]([NH:5][CH2:4][C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[OH:1])=[O:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCc1cc(Cl)ccc1O
Agent: O=S(=O)([O-])O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-hydroxy-5-chlorobenzylamine (1.22 g, 4.77 mmol assuming the bisulfate salt), (BOC)2O (1.56 g, 7.16 mmol) and N-methylmorpholine (1.05 ml, 9.54 mmol) in DMF (10 ml) was stirred for 5 h at r.t. The reaction was partitioned between water and ethyl acetate and the organic layer was washed with 5% KHSO4 solution (2 times), sodium hydrogen carbonate solution and brine, dried (Na2SO4) and evaporated in vacuo to a solid. The crude product was recrystallized from ethyl acetate/hexanes (1:5, 12 ml) to give the title compound:
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:12]=1[CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]2[N:24]([C:25](=[O:35])[C:26]=1[O:27]CC1C=CC=CC=1)[CH2:23][CH2:22][O:21][C:20]2([CH3:37])[CH3:36])=[O:16])=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:12]=1[CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]2[N:24]([C:25](=[O:35])[C:26]=1[OH:27])[CH2:23][CH2:22][O:21][C:20]2([CH3:37])[CH3:36])=[O:16]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CN=[N+]=[N-])c(OCc1ccccc1)c2=O
Agent: [Pd]
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CN)c(O)c2=O

Procedure:
The title compound can be prepared by hydrogenolysis (H2, 110% Pd—C) of intermediate 195, (R)-N-(2-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide. 1H NMR (400 MHz, MeOD) δ ppm: 7.54 (1H, dd, J=7.0 Hz), 7.25–7.13 (2H, m), 4.62 (2H, m), 4.17 (1H, d, J=15.6 Hz), 4.07 (2H, m), 3.99 (2H, m,), 3.23 (2H, d, J=3.1 Hz), 2.79–2.59 (3H, m), 2.14 (1H, m), 1.66 (6H, s). HRMS calcd for C22H27N5O5F: 460.1996. found 460.2014.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[N:13]3[C:14](=[O:20])[NH:15][C:16]4=[CH:17][CH:18]=[CH:19][C:11](=[C:12]34)[O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:21][N:22](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[O:20]=[C:14]1[N:13]2[CH:8]([C:7]3[C:2]([C:21]#[N:22])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH2:9][O:10][C:11]3=[C:12]2[C:16](=[CH:17][CH:18]=[CH:19]3)[NH:15]1
Reactant: O=c1[nH]c2cccc3c2n1C(c1cccnc1Br)CO3
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ncccc1C1COc2cccc3[nH]c(=O)n1c23
Temperature: 160 °C

Procedure:
A suspension of 4-(2-bromopyridin-3-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (964 mg, 2.90 mmol), zinc cyanide (1.00 g, 8.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (335 mg, 0.290 mmol) in N,N-dimethylformamide (20.4 mL) was degassed and heated in a microwave at 160° C. for 20 min. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. The crude product was suspended in hot ethyl acetate and diluted with hexanes to twice the volume, which resulted in the precipitation of a solid. The solid was collected by filtration and washed with ethyl acetate to give the desired product (656 mg). The filtrate was concentrated to a residue which was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product that was combined with the precipitated material (0.709 g total, 88% combined yield) as a racemic mixture. LCMS calculated for C15H11N4O2 (M+H)+: m/z=279.1. found: 278.9.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=1)=C.O.I([O-])(=O)(=O)=[O:15].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:15])[N:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c(nn1)OCCC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cc2c(nn1)OCCC2
Temperature: 25 °C
Reaction time: 4.75 h
Yield: 54.3 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro-5H-pyrano[2,3-c]pyridazine (100 mg, 0.617 mmol) in 1,4-dioxane (5.5 ml)/water (1.1 ml) was cooled in ice/water and treated with sodium periodate (306 mg, 1.43 mmol) and a 4% aqueous solution of osmium tetroxide (0.55 ml). The mixture was allowed to warm to room temperature after an hour, and after a total of 4.75 hours stirring, the solvent was evaporated. 1,4-Dioxane was added and evaporated, followed by dichloromethane and the mixture briefly held in an ultrasonic bath. The whole mixture was applied to a silica gel column and eluted with ethyl acetate to give product (55 mg, 54%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[C:7](=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[N:13]([CH3:15])[N:14]=2)[N:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH3:3].[OH-].[K+].Br[CH2:28][CH2:29][CH3:30]>CS(C)=O>[CH2:1]([N:4]([CH2:28][CH2:29][CH3:30])[C:5]1[C:6]2[C:7](=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[N:13]([CH3:15])[N:14]=2)[N:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH3:3]
Reactant: CCCNc1nc(C)nc2c(-c3c(C)cc(C)cc3C)n(C)nc12
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCN(CCC)c1nc(C)nc2c(-c3c(C)cc(C)cc3C)n(C)nc12
Temperature: 60 °C

Procedure:
A mixture of the product of step F (400 mg, 1.2 mmol), powder KOH (1.0 g) and 1-bromopropane (1 mL ) in 2 mL of DMSO was heated at 60° C. for 8 hours. The excess bromopropane was then evaporated. The mixture was partitioned between water and ether. The aqueous layer was separated and extracted with ether. The combined ether extracts were washed with water and brine, dried over Na2SO4 and concentrated to an oil. The oil was purified through silica gel column chromatography to give 260 mg of the title compound as an oil. 1H NMR (CDCl3): d 0.97 (t, 6 H), 1.76 (m, 4 H), 1.96 (s, 6 H), 2.32 (s, 3 H), 2.45 (s, 3 H), 3.77 (s, 3 H), 3.40-4.30 (br, 4 H), 6.95 (s, 2 H) ppm. The hydrochloride salt prepared in Ether/HCl melted at 210-13° C.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[NH2:12].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[S:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[NH:12][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc2cccnc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc2cccnc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 147-E (0.22 g, 1.00 mmol) in pyridine (5.0 mL) was stirred at rt for 30 min, to which was added benzenesulfonyl chloride (0.135 mL, 1.05 mmol) and the reaction mixture was stirred at rt for 4 h. Another portion of benzenesulfonyl chloride (0.030 mL, 0.235 mmol) was added and the reaction mixture stirred at rt for 72 h. Water and saturated sodium bicarbonate solution were added and the mixture was extracted with dichloromethane, dried over sodium sulfate and evaporated in vacuo to afford a residue.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc([N+](=O)[O-])c2)cc1

Procedure:
Analogously to Method D, 1.0 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.417 g of 1-chloromethyl-3-nitrobenzene are used to obtain the title compound as a slightly yellowish oil. Rf=0.37 (1:2 EtOAc heptane); Rt=6.05.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[S:4][CH:5]=[C:6]([Sn](C)(C)C)[N:7]=1.[Br:13]C1SC=C(Br)N=1.O>CN(C=O)C>[CH3:1][N:2]([CH3:12])[C:3]1[S:4][CH:5]=[C:6]([Br:13])[N:7]=1
Reactant: Brc1csc(Br)n1
Reactant: CN(C)c1nc([Sn](C)(C)C)cs1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1nc(Br)cs1
Temperature: 155 °C
Yield: 89 %

Procedure:
Synthesis of 2-Dimethylamino-4-trimethylstannylthiazole 386 as illustrated in FIG. 53. 2,4-Dibromothiazole (358; 1.0 equiv) was dissolved in DMF (0.1 M) and heated at 150-160° C. for 8 h, upon which completion of the reaction was indicated by TLC. The mixture was poured into water and extracted with ether (2×). Drying (MgSO4) and evaporation of the solvents gave 2-dimethylamino-4-bromothiazole 385, which was isolated after flash column chromatography (silica gel, 5% EtOAc in hexanes) in 89% yield.
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:10][C:9]=1[N+:28]([O-])=O)[C:3]([O:5]C)=O.O>C(O)(=O)C.[Fe]>[Cl:1][CH:2]1[CH2:7][C:8]2[C:9](=[CH:10][C:11]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]3=[O:27])=[C:12]([F:14])[CH:13]=2)[NH:28][C:3]1=[O:5]
Reactant: COC(=O)C(Cl)Cc1cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)CC(Cl)C(=O)N3)c1=O
Yield: 221.3 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of this Example, using 2.9 grams (0.006 mole) of methyl 2-chloro-3-[5-fluoro-2-nitro-4-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl]propanoate, 2.0 grams (0.036 g-atom) of iron powder, and 5 mL of water in 50 mL of acetic acid. The product from this reaction was combined with that from another run (0.014 mole) of this reaction. The combination was subjected to column chromatography on silica gel. Elution was accomplished using heptane, 1:1 heptane-ethyl acetate, and ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 5.2 grams of 3-(3-chloro-6-fluoro-3,4-dihydroquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]12[C:7]([CH3:9])([CH3:8])[CH:6]1[C:5](=[O:10])[CH:4]=[C:3]([CH3:11])[CH2:2]2.[CH3:12][SH:13]>>[CH3:12][S:13][C:3]1([CH3:11])[CH2:4][C:5](=[O:10])[CH:6]2[C:7]([CH3:8])([CH3:9])[CH:1]2[CH2:2]1
Reactant: CS
Reactant: CC1=CC(=O)C2C(C1)C2(C)C
Product: CSC1(C)CC(=O)C2C(C1)C2(C)C

Procedure:
In accordance with the procedure of Example 8 car-3-en-5-one is reacted with methylmercaptan by heating the reaction mixture in a suitable pressure-vessel for 3 hours to yield 3-methylthio-caran-5-on, boiling point ca 70° at 0.5 mm Hg, nD20 = 1.5224.
Reaction SMILES: [OH:1][C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[CH:4][O:3]1.[CH3:25]O>>[CH3:25][O:1][C:2]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=2)=[CH:4][O:3]1
Reactant: O=C(O)CCc1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Reactant: CO
Product: COC1(c2ccccc2)OC=C(c2ccc(CCC(=O)O)cc2)C1=O
Yield: 83 %

Procedure:
A solution of 3.36 g of 2-hydroxy-2-phenyl-4-[4-(2-carboxyethyl)phenyl]-3(2H)-furanone in 150 ml of methanol was heated under reflux under a nitrogen atmosphere for 17 hrs. The reaction mixture was evaporated and the residue was recrystallized from methylene chloride-petroleum ether to give 2.28 g (83%) of 2-methoxy-2-phenyl-4-[4-(2-carboxyethyl)phenyl]-3-(2H)-furanone as colorless crystals, m.p. 117°-120°C, after drying at 50°C for 1 hr. under vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH2:21]Br>C(#N)C>[Br:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(OCCBr)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-hydroxybenzoate D45 (5 g) and K2CO3 (12.48 g, 90 mmol) in Acetonitrile (150 mL) stirred under nitrogen was added 1,2-dibromoethane (33.9 g, 181 mmol). The reaction mixture was stirred at 60° C. overnight. The reaction mixture was filtered, concentrated to give the crude as clear oil. The crude was purified to give the expected product D46 in 4.2 g, eluting with Petroleum oil/EtOAc=3/1. LCMS Retention time=1.76 mins, [M+H]+273 (5 min run)
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:14]=1[C:15]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]1=2)=[O:16]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: Ic1cnc2c(c1)NCCN2
Product: O=C(c1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Yield: 47 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (614 mg) was reacted with 2,5-difluorobenzoyl chloride as in General Procedure 2 to give the title compound as an off-white foam (47% yield). M.p. foam, LCMS: m/z=402.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.70-1.90 (m, 2H), 3.50-3.65 (m, 2H), 5.29 (bs, 1H), 6.99 (s, 1H), 7.10-7.18 (m, 2H), 7.20-7.25 (m, 1H), 7.99 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>>[CH:18]1([NH:21][S:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:16])=[O:15])[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)CCCCCCCCCCCCBr
Product: O=S(=O)(CCCCCCCCCCCCBr)NC1CC1
Yield: 96.6 %

Procedure:
The reaction was carried out in the same manner as in Preparation Example 3 except for using 12-bromododecanesulfonyl chloride (2.92g, 8.4 mmol) in place of 6-bromohexanesulfonyl chloride, and cyclopropylamine (1.08g, 18.5 mmol), to give N-cyclopropyl-12-bromododecanesulfonamide (2.99 g) as colorless crystals.