Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH2:20][OH:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:12]1([CH2:11][CH2:10][C:9]2([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:21][CH2:20][CH2:19][O:18]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1ccc(CCC2(CCc3ccccc3)OCCO2)cc1

Procedure:
A solution of 135 mg (0.6 mmol) of 1,5-diphenyl-3-pentanone, 0.2 ml of ethylene glycol, and 10 mg of p-toluene sulfonic acid monohydrate was refluxed with azeotropic removal of water. After separation of water was completed, the solution was diluted with ethyl acetate, washed sequentially with aqueous NaHCO and water, dried over Na2SO4, and concentrated to provide the desired compound. 1H NMR (CDCl3) δ2.0 (m, 4H), 2.71 (m, 4H), 4.03 (s, 4H), 7.15-7.3 (m, 10H). Mass spectrum: (M+H)+ =283.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O.CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8.00 g. of p-chlorocinnamic acid and 4.72 ml. of thionyl chloride in 50 ml. ether is added 1.01 ml. of dimethyl formamide. Two liquid phases are then formed and the reaction mixture is stirred overnight at room temperature. The upper phase is decanted and the solvent evaporated from it to yield p-chlorocinnamoyl chloride.
Reaction SMILES: C([O:3][C:4](=[O:11])[C:5]([CH3:10])=[CH:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>O.CCO>[CH3:10][C:5](=[CH:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:11])=[O:3]
Reactant: CCOC(=O)C(C)=CC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=CC(C)C)C(=O)O
Yield: 99.1 %

Procedure:
A mixture of 2,4-dimethylpent-2-enoic acid ethyl ester (116 g, 742 mmol) and KOH 85% (147 g, 2.23 mol) in water/EtOH (1:1, 2.0 L) was refluxed for 1 d. The EtOH was stripped off on a rotary evaporator, and the remaining mixture was washed with Et2O. The combined ethereal washings were extracted with 2 N aq. NaOH (100 ml), and all aqueous solutions were combined. Under cooling with an ice/water bath, conc. aq. H3PO4 (200 ml) was added to adjust the combined aqueous solutions to pH 3, and the product was extracted with Et2O (200 ml). The ethereal solution was washed with water (200 ml) and brine (25 ml). After drying (Na2SO4), the solvent was evaporated in a rotary evaporator to furnish 94.2 g (99%) of 2,4-dimethyl-pent-2-enoic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:4][CH:3]=1.C(O)COCCOCCO.O.[NH2:27][NH2:28]>O>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:6]=[N:7][C:2]([NH:27][NH2:28])=[CH:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(Nc2ccc(Cl)nn2)c1
Reactant: NN
Solvent: O
Solvent: OCCOCCOCCO
Product: NNc1ccc(Nc2cccc(Cl)c2)nn1
Temperature: 25 °C

Procedure:
(Step 1-ii) 6-chloro-N-(3-chlorophenyl)pyridazin-3-amine (88.1 g, 367 mmol) was suspended in 1:6 triethylene glycol/hydrazine hydrate and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, diluted with water and a solid filtered off. This solid was triturated with Et2O to give the product, N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine, as a brown solid (60 g, 254 mmol, 69% yield): 1H NMR (500 MHz, DMSO-d6) 9.23 (s, 1H), 8.09 (t, J=1.8 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.24 (t, J=8.1 Hz, 1H), 7.08 (d, J=9.4 Hz, 1H), 7.00 (d, J=9.4 Hz, 1H), 6.85 (dd, J=1.3, 7.8 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:58]=[CH:57][C:7]([O:8][P:9]2([O:47][C:48]3[CH:53]=[CH:52][C:51]([N+:54]([O-])=O)=[CH:50][CH:49]=3)[N:14]=[P:13]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:12]=[P:11]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-])=O.NC1C=CC=CC=1.[H][H]>[Pt]=O.C1CCCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][P:9]2([O:47][C:48]3[CH:49]=[CH:50][C:51]([NH2:54])=[CH:52][CH:53]=3)[N:14]=[P:13]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[N:12]=[P:11]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:10]=2)=[CH:57][CH:58]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OP2(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(c3ccccc3)(c3ccccc3)=N2)cc1
Agent: O=[Pt]
Solvent: Nc1ccccc1
Solvent: C1CCCCC1
Product: Nc1ccc(OP2(Oc3ccc(N)cc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=NP(c3ccccc3)(c3ccccc3)=N2)cc1
Yield: 78 %

Procedure:
2,2,4,4-Tetra(p-nitrophenoxy)-6,6-diphenylcyclotriphosphazene (16.01 g, 0.021 moles), platinum oxide catalyst (0.09 g, 0.0004 moles), and 50 mls aniline are added to a 500 ml Fischer-Porter reaction vessel. The reaction is heated to 50° C. at 50-60 psi of hydrogen pressure for 65 hours. The reaction mixture is then cooled and concentrated to about 25 mls under vacuum. The concentrate is poured into 250 mls cyclohexane, and a brown coagulate forms. The solvent is decanted off and the residue is poured into hot cyclohexane and allowed to cool until stirring becomes difficult. The solvent is decanted off and the residue chilled for about 20 minutes. Recrystallization from o-dichlorobenzene yields a pale brown precipitate, which is boiled in cyclohexane for two hours. A solid is recovered (10.8 g, 78% yield). 31P NMR (THF) δ21.3(triplet), 10.1(doublet).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:9])=[CH:5][CH2:6][CH2:7][OH:8].Br[CH2:11][CH2:12][CH2:13][C:14]1([O:19][CH2:18][CH2:17][O:16]1)[CH3:15].O>CN(C)C=O>[CH2:17]1[CH2:18][O:19][C:14]([CH2:13][CH2:12][CH2:11][O:8][CH2:7][CH2:6][CH:5]=[C:4]([CH3:9])[CH3:3])([CH3:15])[O:16]1
Reactant: CC(C)=CCCO
Reactant: CC1(CCCBr)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCCOCCCC1(C)OCCO1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
14 g of sodium hydride in a 50% suspension in oil were added to a solution of 28 g of 4-methyl-3-pentenol [Julia et al, Bull. Soc. Chim., (1960), p. 1072] in 250 ml of dimethylformamide and after stirring the mixture for 1 hour, 66 g of 5-bromo-2,2-ethylenedioxy-pentane were added thereto while keeping the temperature below 35° C. The mixture was stirred at room temperature for 17 hours and the reaction mixture was then poured into water. The mixture was extracted with petroleum ether (b.p.= 40°-75° C.) and the organic phase was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was rectified to obtain 20 g of 2,2-ethylenedioxy-10-methyl-6-oxa-9-undecene in the form of a colorless liquid with a boiling point of 75° C. at 0.05 mm Hg.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:27])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[C:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:36]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:27])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]4)=[CH:16][CH:17]=3)=[C:9]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[S:8][C:7]=2[CH:36]=1
Reactant: CCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)CC1
Yield: 72 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[1-ethylpiperidin-4-oxy]benzoyl)benzo[b]thiophene (502 mg, 1.00 mmol), ethane thiol (5.00 mmol), and aluminum chloride (800 mg, 6.00 mmol) were converted to 341 mg (72%) of the title compound by the procedure of Example 16. MS(FD) 571(M+). IR (CHCl3) ν max 3300, 2971, 1598, 1249, 1165.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CCCCCCC>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][NH:10][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCl
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: C[Si](C)(C)CNCc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
(3-(Trifluoromethyl)phenyl)methanamine (25 g, 143 mmol), (chloromethyl)trimethylsilane (19.92 mL, 143 mmol), and triethylamine (23.87 mL, 171 mmol) were combined neat. The resultant reaction mixture was refluxed overnight. The reaction was cooled to room temperature, and heptane (150 mL) was added. The HCl salts were removed by filtration, washing with heptane. The solvent was removed under reduced pressure, and the product was isolated by vacuum distillation (bp 70-90° C./3.2 torr) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.59 (s, 1H), 7.53-7.38 (m, 3H), 3.86 (s, 2H), 2.04 (s, 2H), 1.34 (s, 1H), 0.06 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][N:4]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([SH:29])[C:23](=[CH:27][CH:28]=1)[C:24](O)=[O:25]>N1C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]2[C:24](=[O:25])[N:2]=[C:1]([C:3]3[CH:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[CH:6]=[CH:5][N:4]=3)[S:29][C:22]=2[CH:21]=1
Reactant: O=C(O)c1ccc(Cl)cc1S
Reactant: CCOP(=O)(CCc1ccnc(C#N)c1)OCC
Solvent: c1ccncc1
Product: CCOP(=O)(CCc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1)OCC
Yield: 15.3 %

Procedure:
Diethyl 2-(2-cyano-4-pyridyl)ethylphosphonate (1.7 g, 6.4 mmol) and 4-chlorothiosalicylic acid (2.4 g, 12.8 mmol) were dissolved in pyridine (30 ml), and the mixture was refluxed for 13 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-chloroform (1:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.43 g, 15%) as white crystals.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:18]([Cl:19])=[CH:17][C:6]2[CH:7](Cl)[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[F:1][C:2]([F:21])([F:20])[C:3]1[C:18]([Cl:19])=[CH:17][C:6]2[CH:7]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1
Reactant: CN1CCNCC1
Reactant: FC(F)(F)c1cc2c(cc1Cl)C(Cl)Cc1ccccc1S2
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2Cc3ccccc3Sc3cc(C(F)(F)F)c(Cl)cc32)CC1
Yield: 56 %

Procedure:
A mixture of 7-trifluoromethyl-8,10-dichloro-10,11-dihydrodibenzo(b,f)thiepine (2.89 g), 1-methylpiperazine (1.8 ml) and chloroform (2.5 ml) was refluxed for 7 hours. The chloroform was evaporated under diminished pressure, the residue dissolved in benzene (30 ml), washed with water, and the benzene layer separated and shaken with an excess of 3 N-HCl. The precipitated hydrochloride was filtered, added to the aqueous layer of the filtrate and the base liberated by addition of ammonium hydroxide. It was extracted with benzene and the conventional work-up procedure yielded 1.93 g (56%) of the crude 7-trifluoromethyl-8-chloro-10-(4-methylpiperazino)-10,11-dihydrodibenzo(b,f)thiepine. Neutralization with maleic acid in ethanol followed by addition of ether yielded the crystalline maleate which was crystallized from ethanol; m.p. 197°-200° C.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CN=C1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].CO>CN(C)C=O>[Si:18]([O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCC1CC=CCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC1CC=CCC1)(c1ccccc1)c1ccccc1
Reaction time: 22 h

Procedure:
3-Cyclohexene-1-methanol (5.0 g) was dissolved in N,N-dimethylformamide (50 ml), and imidazole (3.93 g) and tert-butylchlorodiphenylsilane (14 ml) were added to stir the mixture for 22 hours. After adding methanol, the solvent was distilled off under reduced pressure, and water was added to the residue to conduct extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=30:1) to obtain (±)-4-(tert-butyldiphenylsilyloxymethyl)-1-cyclohexene (16.1 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][C:16]2[S:17][C:18]([Cl:21])=[CH:19][N:20]=2)(=[O:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][C:16]2[S:17][C:18]([Cl:21])=[CH:19][N:20]=2)(=[O:13])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61818.2 %

Procedure:
To a solution of methyl 2-chloro-4-{[(5-chloro-1,3-thiazol-2-yl)amino]sulfonyl}benzoate (Preparation 36, 410 mg, 1.1 mmol) in dioxane (4 ml) was added a solution of sodium hydroxide (93 mg, 2.32 mmol) in water (1.5 ml) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 ml), added to concentrated HCl (10 ml) and stirred for 10 minutes at room temperature for 15 minutes. The resultant precipitate was collected by filtration to yield the title compound (239 mg, 0.68 mol, 62%).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]1[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[C:44]([O:51][CH3:52])[CH:43]=[CH:42][CH:41]=1>CC#N>[CH2:49]([O:48][C:46](=[O:47])[C:45]1[C:44]([O:51][CH3:52])=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:39][N:18]([CH2:17][C:9]1[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH3:50]
Reactant: CCOC(=O)c1c(CBr)cccc1OC
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1c(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cccc1OC
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.409 g, 1.08 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.38 mL, 2.18 mmol) followed by a solution of ethyl 6-(bromomethyl)-2-methoxybenzoate (0.454 g, 1.66 mmol) in CH3CN (6 mL). The resultant mixture was heated to 60° C. for 22 hours then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (50 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (25:1 CH2Cl2—CH3OH) followed a further chromatographic purification by column chromatography on silica gel (2:1 hexanes-EtOAc) and radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.38 g (62%) of a white solid.
Reaction SMILES: [H-].[Na+].CCOCC.[CH3:8][CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12]CC)=[O:11].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([CH3:32])=[CH:27][CH:28]=2)[CH:23]=1.[NH4+].[Cl-].[OH-].[K+]>C1COCC1.O>[CH3:8][C:9]([CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([CH3:32])=[CH:27][CH:28]=2)[CH:23]=1)([C:15]([OH:17])=[O:16])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Cc1ccc2ccc(CBr)cc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc2ccc(CC(C)(C(=O)O)C(=O)O)cc2c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred suspension of 3.6 g NaH (90 mmol, 60% in mineral oil) in 200 ml Et2O 16.2 ml (94 mmol) of diethyl 2-methylmalonate was added slowly with cooling. After 2 h stirring at 20 C, solution of 21.2 g (90 mmol) of 2-(bromomethyl)-7-methylnaphthalene (prepared according Gorsane, M.; Martin, R. H.; Bull. Soc. Chim. Belg.; 94; 3; 1985; 205-214.) in 20 ml of THF was added, resulting mixture was stirred overnight and decomposed by addition of saturated NH4Cl solution. Organic phase was separated, aqueous—extracted twice with 100 ml portions of ether. Combined extracts were evaporated, residue was dissolved in 150 ml methanol and solution of KOH (20 g, 360 mmol) was added slowly. Mixture was refluxed for 5 h, then evaporated to dryness and resulting semisolid was dissolved in warm water (300 ml). Solution was extracted three times with 100 ml portions of ether, then acidified carefully by addition of 10% HCl. Precipitate of acid 2 was collected and dried, yielded 18.8 g (76%) of yellowish powder.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CO>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(I)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
To a solution of 4-iodo-2-(trifluoromethyl)benzoic acid (for a preparation see Intermediate 31)(16.7 g, 52.8 mmol) in THF (150 ml) at ambient temperature under nitrogen was added 1.0 M borane-tetrahydrofuran complex (100 ml, 100 mmol, Aldrich) dropwise. The solution was heated to 80° C. for 1.5 h. To the solution at ambient temperature was added methanol (75 ml) and then heated to 80° C. for 1 h. The solvent was removed in vacuo to leave a mobile oil. The residue was partitioned between ethyl acetate (200 ml) and 2 N aqueous HCl (100 ml). The phases were separated and the organic phase washed with 2 N aqueous sodium hydroxide (100 ml), brine (50 ml), then dried (MgSO4), filtered and the solvent removed in vacuo to give [4-iodo-2-(trifluoromethyl)phenyl]methanol as a pale brown solid (14.8 g).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1>C1COCC1>[Cl:11][C:12]1[N:13]=[N:14][C:15]([O:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)=[CH:16][CH:17]=1
Reactant: OCc1ccccn1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(OCc2ccccn2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a solution of NaH (1.44 g, 36 mmol, 60% in mineral oil) in THF (15 mL) was added pyridin-2-ylmethanol (1.16 ml, 12 mmol) and the mixture was stirred for 30 min at rt. Then 3,6-dichloropyridazine (1.79 g, 14 mmol) was added and the mixture was stirred at 55° C. for 4 hours. The reaction was quenched with water and sat. NaHCO3 was added. The product was then extracted with EtOAc, dried over MgSO4 filtered and evaporated. The residue was purified on silica gel(Eluent: 80% EtOAc in hexanes) to give 3-chloro-6-(pyridin-2-ylmethoxy)pyridazine as a white solid (1.64 g, 62%). 1H NMR (300 MHz, dMSO): δ 5.57 (s, 2H), 7.35-7.38 (m, 1H), 7.48-7.54 (m, 2H), 7.82-7.88 (m, 2H), 8.57-8.59 (dd, 1H); MS (M+H, 222).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([C:12]#[N:13])=[C:8]([OH:11])[CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[C:15]([N:17]=[C:18]([S-:21])[S:19][CH3:20])#[N:16].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:14])[CH:7]([C:12]#[N:13])[C:8]([C:9]1[S:21][C:18]([S:19][CH3:20])=[N:17][C:15]=1[NH2:16])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C#N)=C(O)CCl
Reactant: CSC([S-])=NC#N
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1nc(N)c(C(=O)C(C#N)C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-chloro-2-cyano-3-hydroxy-but-2-enoic acid tert-butyl ester Compound 1c (51.3 g, 236 mmol) at 0° C. in acetone (750 mL) was added potassium methyl N-cyanodithioimidocarbonate Compound 1e (40.2 g, 236 mmol). After 1 hr the reaction was allowed to warm to RT. The reaction mixture was evaporated down after stirring for 18 hrs. The resulting residue was extracted with ethyl acetate from saturated NaHCO3. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure to yield a tan foam, 3-(4-amino-2-methylsulfanyl-thiazol-5-yl)-2-cyano-3-oxo-propionic acid tert-butyl ester Compound 1h, 72.2 g. 1H NMR (CDCl3) δ 4.34 (br s, 2H), 3.14 (br s, 1H), 2.70 (br s, 3H), 1.47 (br s, 9H). MS 314 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH3:28])[CH:22]=3)=[C:15]([F:29])[CH:14]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH3:28])[CH:22]=3)=[C:15]([F:29])[CH:14]=2)=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(Br)ccc1Nc1cc(F)c(-c2ccc(Cl)c(C)c2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1Nc1ccc(Br)cc1CO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask was charged with methyl 5-bromo-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)benzoate (7.15 g, 14.94 mmol). A septum was attached and the flask was flushed with N2. To the flask was added THF (149 ml) and the solution was cooled to 0° C. An ethyl ether solution of lithium aluminum hydride solution (17.92 ml, 17.92 mmol, 1M) was added dropwise via syringe to generate an orange solution. After 10 minutes, water (0.68 mL), and 15% NaOH (0.68 mL) were added. The mixture was stirred 10 minutes and then an additional 2.0 mL water was added to generate a white precipitate. The mixture was filtered through a plug of silica and the mother liquor was concentrated to give a tan foam. This was used in the next reaction without further purification. (ESI) 450.0 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:13]=2[O:15][CH3:16])[N:8]([CH2:23][CH3:24])[CH:7]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:23]([N:8]1[C:9]2[C:14](=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[C:6]([CH2:4][CH2:3][N:2]([CH3:25])[CH3:1])=[CH:7]1)[CH3:24]
Reactant: CCn1cc(C(O)CN(C)C)c2c(OC)cc(-c3ccccc3)cc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(CCN(C)C)c2c(OC)cc(-c3ccccc3)cc21
Reaction time: 0.33 h

Procedure:
36-5 (68 mg, 0.2 mmol) was dissolved in DCM (2 mL) and triethylsilane (0.32 mL, 2.0 mmol) was added at 0° C. Trifluoroacetic acid (126 uL, 1.6 mmol) was added dropwise. After 20 minutes, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and then diluted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated. The resulting residue was purified on silica gel column chromatography eluting with DCM/methanol (0-10%) containing 0.1% NH4OH to give the desired product. The product was acidified with HCl to afford 36-6 (19.6 mg, 27%) as an off-white solid. 1H NMR (300 MHz, D2O): δ (ppm) 7.62 (m, 2H), 7.42-7.24 (m, 4H), 7.06 (s, 1H), 6.78 (s, 1H), 4.04 (q, J=7.5 Hz, 2H), 3.88 (s, 3H), 3.31 (t, J=8.4 Hz, 2H), 3.12 (t, J=7.5 Hz, 2H), 2.76 (s, 6H), 1.24 (s, 7.5 Hz, 3H). LCMS: calc 322.4 and found: 323.1 [MH]+.