Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].Cl.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C:13](=O)[CH2:12]2.N12CCN(CC1)CC2.S([O-])([O-])(=O)=O.[Mg+2]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][C:6]1[CH:7]=[CH:8][C:2]2[C:12]3[N:11]4[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]4)[C:13]=3[NH:4][C:3]=2[CH:5]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Cc1ccc(I)c(N)c1
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Product: Cc1ccc2c3c([nH]c2c1)C1CCN3CC1

Procedure:
2-Iodo-5-methylaniline (1.0 g, 4.29 mmol; Amfinecom), quinuclidin-3-one hydrochloride (1.24 g, 7.67 mmol; Aldrich), palladium(II) acetate (48 mg, 0.22 mmol; Aldrich), 1,4-diazabicyclo[2.2.2]octane (DABCO; 1.73 g, 15.4 mmol; Aldrich) and magnesium sulfate (0.88 g, 7.31 mmol) were processed as described in Example 205A to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 1.52-1.63 (m, 2H), 1.94-2.05 (m, 2H), 2.40 (s, 3H), 2.59-2.71 (m, 2H), 3.26 (ddd, J=12.2, 8.5, 4.3 Hz, 2H), 3.40 (quintet, J=2.9 Hz, 1H), 6.85 (d, J=7.3, 0.7 Hz, 1H), 7.14 (s, 1H), 7.42 (d, J=7.9 Hz, 1H); MS (DCI) m/z 213 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[OH:12][CH:13]([CH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)[C:14]([CH3:25])([CH3:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>ClCCl>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([CH3:24])([CH3:25])[CH:13]([OH:12])[CH2:26][C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N+:28]=2[O-:9])=[CH:23][CH:22]=1)#[N:21]
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1cnccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1cncc[n+]1[O-]
Reaction time: 24 h
Yield: 30.4 %

Procedure:
0.18 g of m-chloroperbenzoic acid was added to a stirred solution of 0.28 g of 4-[2-hydroxy-1,1-dimethyl-3-(2-pyrazinyl)propoxy]benzonitrile in 10 ml of dichloromethane. After 16 hours a further 36 mg of m-chloroperbenzoic acid were added and the mixture was stirred for 24 hours. The solvents were then removed by evaporation and the residue was chromatographed on silica gel using diethyl ether/methanol (95:5) for the elution to give 0.09 g of 2-[3-(4-cyanophenoxy)-2-hydroxy- 3-methylbutyl]-pyrazine 1-oxide in the form of a white solid of melting point 103°-104° C. (from diethyl ether).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[N:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH:23]=3)[N:21]=[C:17]2[C:16]([CH3:29])=[N:15][CH:14]=1.C(N(C(C)C)C(C)C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>CCO.ClCCl>[CH3:12][C:13]1[N:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]4[C:2]([CH3:11])=[C:3]([C:5]5[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:28]=[C:24]4[CH:23]=3)[N:21]=[C:17]2[C:16]([CH3:29])=[N:15][CH:14]=1.[C:41]([OH:43])([C:40]([F:45])([F:44])[F:39])=[O:42]
Reactant: Cc1ncc(C)n2nc(-c3ccnc(N)c3)nc12
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(C)n2nc(-c3ccn4c(C)c(-c5ccccc5)nc4c3)nc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
2-bromo-1-phenylpropan-1-one (0.032 ml, 0.208 mmol) was added to a solution of 4-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)pyridin-2-amine (0.025 mg, 0.104 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.056 ml, 0.312 mmol) in EtOH (2.5 mL) and the mixture was heated under standard microwave conditions at 110° C. for 4 hours. LC/MS analysis of the reaction mixture indicates reaction completion. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; 30-100% EtOAc/hexanes) to afford a yellow solid. The purified product was dissolved in 5 mL of a 1:1 solution of dichloromethane and trifluoroacetic acid. This mixture was allowed to stir overnight at room temperature. The volatiles were removed in vacuo to give 5,8-dimethyl-2-(3-methyl-2-phenylimidazo[1,2-a]pyridin-7-yl)-[1,2,4]triazolo[1,5-a]pyrazine, 2 TFA (0.0112 g, 0.019 mmol, 18.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=7.5 Hz, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.87 (d, J=7.0 Hz, 2H), 7.78 (dd, J=7.0, 1.8 Hz, 1H), 7.53 (t, J=7.7 Hz, 2H), 7.42 (d, J=7.3 Hz, 1H), 2.87 (s, 3H), 2.78 (s, 3H), 2.74 (s, 3H), LC/MS: (Method 2) Anal. Calcd. for [M+H]+C21H19N6: 355.16. Found: 355.18.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH2:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:26]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[CH2:17][CH2:18][CH2:19]3)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2c(c1)CCC2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)CCC3)c2cc3c(cc21)OCO3
Yield: 59 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (291 mg) and 5-indancarboxaldehyde (190 mg) by the procedure described in example 10 in 59% yield, mp: 146-148° C. 1H NMR (CDCl3): 7.21-7.04 (m, 3H), 6.67 (s, 1H), 6.30 (s, 1H), 5.91 (d, J=1.4, 1H), 5.89 (d, J=1.4, 1H), 5.27 (s, 1H), 5.00 (s, 1H), 4.45 (m, 1H), 2.89 (m, 4H), 2.08 (m, 2H), 2.08 (m, 2H), 1.58-1.55 (m, 6H). Anal. calcd. for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99. Found: C, 72.25; H, 6.59; N, 7.89.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(Cl)(=O)OCC.[Cl-].[Na+].[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C.O.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(/C=C/C(=O)O)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(/C=C/CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
1.73 g of (E)-3-(3-cyanophenyl)acrylic acid was suspended in 8.7 ml of tetrahydrofuran. To the suspension was added 1.11 g of triethylamine. To the mixture was dropwise added a solution of 1.14 g of ethyl chlorocarbonate dissolved in 3.0 ml of tetrahydrofuran, at -20° to -10° C. The mixture was stirred for 30 minutes at 0° C. The reaction mixture was mixed with 2 ml of ethyl acetate and 20 ml of a saturated aqueous sodium chloride solution. The organic layer was separated and washed with a saturated aqueous sodium chloride solution to obtain a solution containing a mixed acid anhydride of (E)-3-(3-cyanophenyl)acrylic acid. To this solution was added 380 mg of sodium borohydride with ice-cooling. The mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 20 ml of water and 10 ml of ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/acetone=5/1) to obtain 1.37 g of colorless oily (E)-3-(3-cyanophenyl)allyl alcohol.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25][CH3:26])[CH2:21][CH2:20]4)[CH:14]=3)[C:9]2=[O:27])=CC=1.CO>C(O)(C(F)(F)F)=O>[CH3:26][NH:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:27])[NH:8][CH:17]=[CH:16]3)[CH2:20][CH2:21]1
Reactant: CNC1CCC(Oc2ccc3c(=O)n(Cc4ccc(OC)cc4)ccc3c2)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Temperature: 150 °C

Procedure:
2.46 g of 2-(4-methoxy-benzyl)-6-(4-methylamino-cyclohexyloxy)-2H-isoquinolin-1-one (151) were dissolved in 15 mL of TFA and heated in a microwave oven at 150° C. for 2 h. Methanol was added and the reaction mixture was evaporated. The solution was taken up in 1N HCl and extracted three times with dichloromethane. The combined dichloromethane layers were extracted with 1N HCl twice and the combined HCl layers were lyophilized, the residue was taken up in water and lyophilized again to yield 1.31 g of 6-(4-methylamino-cyclohexyloxy)-2H-isoquinolin-1-one (152) as hydrochloride. Rt=0.81 min (Method B). Detected mass: 273.2 (M+H+).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[OH-].[Na+].S(OC)([O:17][CH3:18])(=O)=O.Cl.[Na+].[Cl-]>O>[CH3:18][O:17][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C@@H:2]([OH:3])[C:1]([OH:11])=[O:10]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1[C@@H](O)C(=O)O

Procedure:
(R)-mandelic acid (4.678 g, 30.75 mmol) was dissolved in 6M NaOH (50 mL, 300 mmol) and dimethyl sulfate (14.6 mL, 154 mmol) was added over 1 hr so that the temperature stayed at 50° C. After another hr of stirring, H2O (50 mL) was added, and the solution was acidified to pH 1 with 12M HCl. The mixture was saturated with NaCl, extracted with EtOAc (3×100 mL), and the extracts dried with Na2SO4. After filtration and evaporation under reduced pressure, the solid was pulverized, refluxed in hexanes (100 mL) for 15 min and hot filtered. The insoluble (R)-mandelic acid (2.71 g, 58%) was recovered, and the hexanes evaporated under reduced pressure to give (R)-2-methoxy-mandelic acid, (R)-3 (1.91 g, 37%) which was used directly in the next step.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[C:7]2[C:14]([C:15](=[O:19])[C:16]([NH2:18])=[O:17])=[C:13]([CH2:20][CH3:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[OH-].[Na+].Cl>CO>[NH2:18][C:16](=[O:17])[C:15]([C:14]1[C:7]2[C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[N:11][CH:10]=[N:9][C:8]=2[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:13]=1[CH2:20][CH3:21])=[O:19]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)ncnc2n1Cc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)ncnc2n1Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of 150 mg (0.317 mmol) of [[5-(aminooxoacetyl)-6-ethyl-7-([1,1′-biphenyl] -2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 10 mL of methanol were treated with 0.95 mL of 2 M sodium hydroxide and heated to reflux for 4 hours. The reaction was cooled to ambient temperature then adjusted to pH 2 by the addition of 1 M HCl. The mixture was concentrated to a minimum volume and the residual liquid decanted from the solids. The solids were dried in vacuo to provide 92 mg (63%) of [[5-(aminooxoacetyl)-6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a tan foam. nmr (300 MHz, dmso-d6) δ1.15 (t, J=7.4 Hz, 3H), 2.64 (q, J=7.4 Hz, 2H), 4.90 (s, 2H), 5.46 (s, 2H), 6.60 (d, J=7.2 Hz, 1H), 7.2-7.6 (m, 9H), 7.99 (s, 1H), 8.43 (s, 1H)
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.O1C2C=CC(NCC3CCCCC3)=CC=2OC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([N:15]([CH2:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[C:13](=[O:14])[NH:12][C:10]3[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc3c(c2)OCO3)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: c1cc2c(cc1NCC1CCCCC1)OCO2
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc3c(c2)OCO3)s1

Procedure:
The title compound was prepared via [2-(3-benzo[1,3]dioxol-5-yl-3-cyclopentylmethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using benzo[1,3]dioxol-5-yl-cyclohexylmethyl-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=O.C([N:31]=[C:32]=[S:33])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][CH2:9][C:10]#[CH:11])[CH:4]=3)[NH:1][C:32](=[S:33])[N:31]=2)=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#CCOc1ccc2[nH]c(=S)nc(-c3ccc(C(C)C)cc3)c2c1
Reaction time: 18 h

Procedure:
A solution of 0.5 g (1.71 mmol) (2-amino-5-prop-2-ynyloxy-phenyl)-(4-isopropyl-phenyl)-methanone and 0.23 ml (1.71 mmol) benzoyl isothiocyanate in 5 ml THF is stirred for 3 h at r.t. before 0.235 g potassium carbonate and 5 ml methanol are added. After stirring for 18 h, the reaction mixture is acidified with 0.1 M aqueous hydrochloric acid and extracted with dichloromethane. After evaporation of the organic phases, the residue is triturated with diethyl ether to give the title compound.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:23]=[C:22]([CH:24]=[O:25])[C:21]([S:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:20][N:19]=1)(=[O:16])=[O:15]>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:23]=[C:22]([CH:24]([CH:1]2[CH2:3][CH2:2]2)[OH:25])[C:21]([S:26][C:27]2[CH:28]=[CH:29][C:30]([S:33]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)(=[O:35])=[O:34])=[CH:31][CH:32]=2)=[CH:20][N:19]=1)(=[O:16])=[O:15]
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(C(O)C2CC2)c(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)cn1)c1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A solution of cyclopropylmagnesium bromide (0.5 M, 1.55 ml, 0.78 mmol) was added to a stirred solution of 2,4-dichloro-N-{4-formyl-5-[4-(piperidine-1-sulfonyl) -phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide (130 mg, 0.22 mmol) in THF (15 ml) and the mixture stirred for 2 hours. The reaction was concentrated under reduced pressure onto silica and the residue purified by flash column chromatography using ethyl acetate 1/1 hexane as eluent to afford 2,4-dichloro-N-{4-(cyclopropyl-hydroxy-methyl)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide as a green foam (74 mg, 54 %). 1H NMR (CDCl3): 8.40 (1H, s, py); 8.18 (1H, d, Ar); 7.51 (3H, m, py and Ar); 7.39 (1H, s, py); 7.34 (1H, d, Ar); 7.06 (2H, d, Ar); 4.50 (1H, d, CHOH); 2.89 (4H, m, 2×CH2N pip); 1.54 (4H, m, 2×CH2 pip); 1.34 (2H, m, CH2 pip); 0.97 (1H, m, CH cprop); 0.39 (4H, m, 2×CH2 cprop).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:10][CH:11]([CH3:17])[CH2:12][CH2:13][C:14](O)=[O:15])[CH2:8][CH3:9].Cl>CCOCC>[CH2:7]([O:10][C@H:11]([CH3:17])[CH2:12][CH2:13][CH2:14][OH:15])[CH2:8][CH3:9]
Reactant: CCCOC(C)CCC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCO[C@H](C)CCCO
Reaction time: 12 h

Procedure:
Then, 10.1 g of LiAlH4 was added to 217 ml of dry ether, and under stirring, a solution of the above 4-propoxyvaleric acid in 44 ml of ether was added dropwise at below 10° C. in 3.5 hours. After the addition, the mixture was raised in temperature to 20°-25° C., stirred for 3 hours and then leftstanding for 12 hours. An aqueous 5%-hydrochloric acid solution was added to acidify the mixture (pH 1), which was then subjected to extraction with ether. The ether layer was washed successively with 5%-NaOH aqueous solution and saturated saline water, followed by drying with anhydrous magnesium sulfate, distilling-off of ether and vacuum distillation to obtain 26 g of (R)-4-propoxypentanol as a fraction at 109°-117° C./35 mmHg.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2=[CH:14][S:15][C:16]([NH2:17])=[C:12]2[C:11](=[O:18])[N:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[C:13]2[C:12](=[C:16]([NH2:17])[S:15][CH:14]=2)[C:11](=[O:18])[N:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:9]=1
Reactant: COc1ccc(-n2nc(NC(=O)OC(C)(C)C)c3csc(N)c3c2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2nc(N)c3csc(N)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a solution of [5-amino-3-(4-methoxy-phenyl)-4-oxo-3,4-dihydro-thieno[3,4-d]pyridazin-1-yl]carbamic acid tert-butyl ester (140 mg, 0.36 mmol, prepared as described in example 33) in dichloromethane (20 ml) was added trifluoroacetic acid (5 ml) and the reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated in vacuo and the residue was dissolved in ethanol and evaporated in vacuo. The semi solid residue was treated with diethyl ether (25 ml) for 16 h, the precipitate was filtered off and dried in vacuo at 50° C. for 16 h affording 30 mg crude title compound. The diethyl ether phase was evaporated and the residue was purified on silica gel (200 ml) using a mixture of ethyl acetate and heptane (3:1) as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 20 mg (19%) of the title compound as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(NCC#CCO)C(O)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NCC#CCCl)C(O)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.81 ml) was added to a solution of N-(4-hydroxy-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (3.32 g) and N,N-dimethylformamide (6 drops) in chloroform (20 ml) at room temperature. The mixture was stirred at 40° C. for 1 hour, washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (5:1) as an eluent to give N-(4-chloro-2-butynyl) -2-hydroxy-2,2-diphenylacetamide (4.12 g) as oil.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[C:16]([C:32]#[N:33])=[C:17]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[S:18][C:12]=2[CH2:11]1)=[O:9])(=O)C>[OH-].[Na+]>[OH:4][CH2:5][CH2:6][O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[C:16]([C:32]#[N:33])=[C:17]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[S:18][C:12]=2[CH2:11]1)=[O:9]
Reactant: COc1ccccc1CCC(=O)Nc1sc2c(c1C#N)CCN(C(=O)OCCOC(C)=O)C2
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1CCC(=O)Nc1sc2c(c1C#N)CCN(C(=O)OCCO)C2

Procedure:
3-Cyano-2-[3-(2-methoxy-phenyl)-propionylamino]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid 2-acetoxy-ethyl ester (Example 31) is stirred in 1N NaOH over night at room temperature. After acidification with aqueous HCl the precipitated product is filtered off and recristalized from ethanol.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]2[NH:11][N:12]([SH:14])[CH:13]=[C:5]2[CH:4]=1.S(OC)(O[CH3:19])(=O)=O>>[CH3:19][S:14][N:12]1[CH:13]=[C:5]2[N:6]([C:7]([S:9][CH3:10])=[N:8][C:3]([S:2][CH3:1])=[CH:4]2)[NH:11]1
Reactant: COS(=O)(=O)OC
Reactant: CSC1=CC2=CN(S)NN2C(SC)=N1
Product: CSC1=CC2=CN(SC)NN2C(SC)=N1

Procedure:
Using the method of Example 28 and starting with 5,7-bis(methylthio)triazolo[1,5-c]pyrimidine-2-thiol (from Example 23) and dimethyl sulfate, a solid was obtained which was recrystallized from an ethyl acetate-hexane mixture to provide 2,5,7-tris(methylthio)triazolo[1,5-c]pyrimidine, m.p. 165°-167° C. Analysis: Calculated for C8H10N4S3 : %C, 37.2; %H, 3.9; %N, 21.7; Found: %C, 37.5; %H, 3.9; %N, 22.0.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[Cl:13].[I-:14].[Na+].N>O1CCOCC1.[Cu](I)I>[Cl:13][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([I:14])=[CH:11]2
Reactant: Oc1cc(Cl)c2ncc(Br)cc2c1
Reactant: [I-]
Agent: I[Cu]I
Agent: N
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cc(Cl)c2ncc(I)cc2c1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
To a stirred mixture of 3-bromo-8-chloro-6-hydroxyquinoline (5.0 g) (preparation described in WO 2004/108663), sodium iodide (5.8 g) and copper iodide (0.37 g) in dioxane (65 ml) is added N,N″-dimethyl-ethane-1,2-diamine (0.34 g) in a sealed tube under argon. The mixture is stirred at 120° C. for 14 h and upon cooling is treated with aqueous ammonia followed by aqueous hydrochloric (to pH 5). Extraction with ethyl acetate, drying of the organic phase over magnesium sulphate, filtration and evaporation under reduced pressure gives the required product ((M+1)+306) that is used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5]Br.[CH2:23]([O:25][P:26]([O:30]CC)[O:27][CH2:28][CH3:29])[CH3:24]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5][P:26](=[O:30])([O:27][CH2:28][CH3:29])[O:25][CH2:23][CH3:24]
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(Oc2c(Cl)cc(CBr)cc2Cl)cc1C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1cc(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c(Cl)c1)OCC
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A mixture of 3,5-dichloro-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl bromide (0.61 g, 1.51 mmol) and triethylphosphite (0.61 g, 3.56 mmol) in DMF (2.0 mL) was heated under reflux for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (3:7) to afford diethyl 3,5-dichloro-4-(3′-iso-propyl-4′-methoxyphenoxy)benzylphosphonate as an oil (0.59 g, 85%): 1H NMR (300 MHz, DMSO-d6): δ 7.55 (s, 2H), 6.88 (d, J=9.0 Hz, 1H), 6.75 (d, J=3.0 Hz, 1H), 6.43 (m, 1H), 4.01 (m, 4H), 3.75 (s, 3H), 3.41 (m, 2H), 3.22 (m, 1H), 1.20 (m, 6H), 1.12 (d, J=6.0 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethyl acetate (4:1); Rf=0.22.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[ClH:13].O1CCOCC1.[C:20](#[N:22])[CH3:21]>>[ClH:13].[C:20]([NH:11][C:10]1[CH:9]=[C:8]([CH3:12])[NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[NH:22])[CH3:21]
Reactant: CCOC(=O)c1[nH]c(C)cc1N
Reactant: CC#N
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c(C)cc1NC(C)=N
Temperature: 50 °C

Procedure:
Ethyl-3-amino-5-methyl-1H-pyrrole-2-carboxylate (58.87 g; 0.35 mol) prepared according to literature [Gangjee A.; Li W.; Yang J.; Kisliuk R. L.; J. Med. Chem. 2008, 51, 68] is suspended in acetonitrile (1750 mL). To the suspension is added dropwise 4M HCl in dioxane (473 mL; 1.89 mol) within 15 minutes. After complete addition the reaction mixture is heated to 50° C. for 18 hours. The reaction mixture is cooled to 10° C., the solid is collected by suction filtration and washed with cold acetonitrile (400 mL). A second crop of product is obtained from the mother liquor after concentration under reduced pressure. The residue is collected with t-butylmethyl-ether. After the suction filtration the solids are combined and dried in vacuum at 50° C. to yield the title compound as off-white solid.