Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH2:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([C@@]1(O)[C@@H](CO)O[C@@](C(=O)C)([N:24]2[C:34]3[N:33]=[C:31]([NH2:32])[NH:30][C:28](=[O:29])[C:27]=3[N:26]=[CH:25]2)[C@]1(C(=O)C)O)(=O)C.Cl>CO>[CH2:6]([N:26]1[C:27]2[C:28](=[O:29])[NH:30][C:31]([NH2:32])=[N:33][C:34]=2[N:24]=[CH:25]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)[C@@]1(O)[C@@](O)(C(C)=O)[C@@H](CO)O[C@@]1(C(C)=O)n1cnc2c(=O)[nH]c(N)nc21
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 22 h
Yield: 76.4 %

Procedure:
Four milliliters of N,N-dimethylformamide and 0.53 ml (2.49 equivalents) of benzyl chloride were added to 0.758 g (1.85 mmols) of triacetylguanosine, and the reaction was conducted at 60° C. for 22 hours. It was identified through liquid chromatography that 69% of the starting material remained. Accordingly, 1.60 ml (10 equivalents in total) of benzyl chloride were further added thereto, and the reaction was conducted at 60° C. for 23 hours and at 70° C. for 5 hours. The temperature was returned to room temperature, and 1.57 ml (10 equivalents) of conc. hydrochloric acid were added to the solution. The reaction was conducted for 2 hours, but the cleavage of the sugar moiety was not completed. Therefore, 1.58 ml (20 equivalents in total) of conc. hydrochloric acid were further added, and the mixture was stirred overnight at room temperature. Ten milliliters of methanol were added to the reaction solution in the slurry state. The mixture was stirred for 2 hours, and then filtered. The crystals were washed twice with 5 ml of methanol, dried at 50° C. under reduced pressure for 5 hours to give 0.444 g of 7-benzylguanine crystals in a yield of 76.4%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.CC(O)CC>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCC(C)O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 118 °C
Yield: 84 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (100 g, 0.38 mol), N-methylpiperazine (250 mL, 2.5 vol) and 2-butanol (200 mL, 2 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was heated to reflux at 118° C. under a nitrogen atmosphere and refluxed overnight. The reaction mixture was allowed to cool to below 55° C. whereupon water (300 mL, 3 volumes) was added to precipitate out the solid. It was isolated by Buchner filtration and the light yellow solid was washed twice with 25% aqueous 2-butanol (100 mL) and then once with 2-butanol (100 mL) and dried to provide olanzapine in 84% yield (98.7 g).
Reaction SMILES: C(OC([P:9]([CH2:14][CH2:15][CH2:16][CH3:17])(=[O:13])[O:10][CH2:11][CH3:12])(OCC)C)C.C(O)C.C[Si](C)(C)Cl>ClCCl>[CH2:14]([PH:9](=[O:13])[O:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCP(=O)(OCC)C(C)(OCC)OCC
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCC[PH](=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 176 g of ethyl 1,1-diethoxyethyl(n-butyl)phosphinate in 540 ml of absolute dichloromethane containing 10% of absolute ethanol is treated with 143.6 g of trimethylchlorosilane. After stirring for 48 hours at room temperature, the solvent is removed in vacuo to afford a pale yellow oil. Distillation in vacuo affords ethyl n-butyl-phosphinate, b.p. 27°-34° (2×10-2 mbar).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:27][C:26]=3[CH3:28])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(C)c2c(c1)CCN2
Agent: Cl
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 160-162° C.; 1H NMR (300 MHz, CDCl3): δ 6.89 (s, 1 H), 6.67 (d, J=2.2 Hz, 1H), 6.59 (d, J=2.2 Hz, 1 H), 4.37 (t, J=7.7 Hz, 2H), 4.29-4.04 (m, 1 H), 3.79 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.07 (s, 3 H), 1.95-1.75 (m, 2 H), 1.08-1.00 (m, 1 H), 0.95 (t, J=7.5 Hz, 3 H), 0.82-0.75 (m, 1 H), 0.57-0.47 (m, 2 H), 0.36-0.29 (m, 1 H); HRMS (ESI) calcd for C20H25N3O2Cl (M+H)+: 374.1635; found m/z 374.1617.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]=[C:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1>C1COCC1>[OH:6][C:7]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: c1cscn1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(O)(c2nccs2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 62.6 %

Procedure:
Isopropylmagnesium chloride/lithium chloride complex (1.3 M, 119 mL, 154 mmol) was added to a flask and cooled to 0° C. and then diluted with 50 mL THF. Thiazole (13.0 g, 154 mmol) was added over 30 minutes making sure the temperature did not exceed 5° C. The orange slurry was stirred for 45 minutes and then cooled to −20° C. and ethyl 4-oxocyclohexane-carboxylate (25.0 g, 147 mmol) in THF (25 mL) was added and then stirred for 50 minutes. The solution was cooled to 5° C. and then quenched with HCl (2 M, 100 mL) and extracted with EtOAc (250 mL). The organic layer was washed with aqueous saturated NaHCO3 solution (100 mL), brine (100 mL), evaporated and purified by flash chromatography on silica gel to afford ethyl 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanecarboylate as an oil (23.6 g, 92 mmol).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[Na].[C:10](#[N:13])[CH:11]=[CH2:12].O>C(O)C>[NH2:13][C:10]1[CH2:11][CH2:12][N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: C=CC#N
Reactant: NNc1ccccn1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: NC1=NN(c2ccccn2)CC1

Procedure:
2-Hydrazinopyridine (0.545 g) was added to a solution of sodium (50 mg; 0.43 atoms) in dry absolute ethanol (2 ml) in a nitrogen atmosphere. Acrylonitrile (0.265 g; 0.32 ml; 1 mol) was added dropwise and the resulting solution heated for 4 hours on the steam bath. The reaction mixture was cooled, giving some crystals, and treated with water (10 ml) to give a suspension of a solid. The solid was collected and washed with water. Recrystallisation from ethanol (ca. 5 ml) gave the title compound m.p. 168°-169.5°. Thin Layer Chromatography: On Al2O3 in CHCl3 gave a single spot Rf 0.18.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:3]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>C(OCC)(=O)C>[NH2:23][CH2:22][CH2:21][NH:24][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:3]=1
Reactant: NCCN
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Solvent: CCOC(C)=O
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(NCCN)nc21
Temperature: 150 °C

Procedure:
250 mg (0.81 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine are dissolved in 5.8 ml (97 mmol) of ethylenediamine and the solution is heated under reflux for 3 hours (oil bath temperature of 150° C.). After cooling to room temperature, the reaction mixture is taken up in ethyl acetate (250 ml) and extracted with water (150 ml). The aqueous phase is extracted twice with ethyl acetate and the combined organic extracts are washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure at 35° C. and the residue is dried under an HV. The crude product is recrystallized from diethyl ether. 2-(2-Amino-ethyl-amino)-6-(3-chloro-phenylamino)-9-ethyl-9H-purine is obtained; Rf=0.22 (methylene chloride:methanol:concentrated aqueous ammonium hydroxide solution=900:100:1); FAB-MS: (M+H)+=322; m.p. 79–80° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[CH3:11].[CH2:12]([O:14][C:15]1[CH:16]=[CH:17][C:18]([F:24])=[C:19](B(O)O)[CH:20]=1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([O:14][C:15]1[CH:16]=[CH:17][C:18]([F:24])=[C:19]([C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]#[N:10])[C:3]=2[CH3:11])[CH:20]=1)[CH3:13]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: Cc1cc(Br)c(C)c(C#N)n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(F)c(-c2cc(C)nc(C#N)c2C)c1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
To a solution of 4-bromo-3,6-dimethyl-pyridine-2-carbonitrile (which may be prepared as described in Description 137) (3.82 g, 18.099 mmol) in MeCN (45 mL) and water (5 mL) in a Smith microwave vessel was added (5-ethoxy-2-fluoro-phenyl)boronic acid (3.6627 g, 19.909 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.3811 g, 0.5430 mmol) and sodium carbonate (3.8367 g, 36.198 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 100° C. for 25 min. The reaction mixture was treated with water and was extracted with DCM twice and the organic layers were collected by passing down a PhaseSep cartridge The solvent was removed by evaporation and the residue was purified by silica gel chromatography (100 g SiO2) eluting with ethyl acetate in iso-hexane (10-60%). Evaporation of desired fractions gave 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carbonitrile (D138) (4.76 g, 17.61 mmol, 97.3% yield);
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)N>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:35])=[O:36])=[CH:30][CH:29]=2)[N:2]=[CH:3][CH:4]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 4-hydrazino-benzenesulfonamide according to example 43 gave the desired product. MS: M=478.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.Cl.[I-:47].[NH2:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N+:59]=2[CH3:64])=[CH:53][CH:52]=1>ClCCCl>[I-:47].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:48][CH2:49][CH2:50][C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][N+:59]=4[CH3:64])=[CH:55][CH:56]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: C[n+]1ccccc1Nc1ccc(CCN)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [I-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(Nc4cccc[n+]4C)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AD using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (50 mg, 0.13 mmol), CDI (33 mg, 0.2 mmol), DIPEA (0.14 mL, 0.81 mmol) and 2-{[4-(2-aminoethyl)phenyl]amino}-1-methylpyridinium iodide hydrochloride (55 mg, 0.14 mmol) in DCE (1.0 mL).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18](CC#N)=[C:17]([O:24][C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.CCN(C(C)C)C(C)C.[C:53]([OH:56])(=[O:55])[CH3:54]>Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:54][C:53]([OH:56])=[O:55])=[C:17]([O:24][C:25]([F:28])([F:26])[F:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC#N)c(OC(F)(F)F)c2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetonitrile (1.9 g, 4.3 mmol) from Step 8 above dissolved in a 2:1 mixture of acetic acid and concentrated aqueous HCl (25 mL). Loss of the Boc group occurred within the first 5 minutes to give an intermediate which had an HPLC retention time of 6.3 min (method A). The solution was then refluxed for 2 h, during which time the 6.3 min peak disappeared and a new peak at 5.9 min appeared. The solvents were removed under reduced pressure. The residue was dissolved in degassed DMF (100 mL) and the solvent was removed under reduced pressure to minimize the amount of residual acetic acid and water in the sample. The crude product, 4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid, was dissolved in DMF (50 mL) and di-tert-butyldicarbonate (1.0 g, 4.6 mmol) and DIEA (2.3 mL, 13 mmol) were added. The solution was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (50 mL). The organic phase was separated, washed with water (2×25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid as a gum (HPLC retention time=10.2 min (method A)).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][CH:14]2[CH:13]([O:21][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])[CH2:12][C:11]1=[CH:27][C:28](OCC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:44]>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH:10]1[CH:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][CH:14]2[CH:13]([O:21][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])[CH2:12][C:11]1=[C:27]([OH:44])[CH3:28])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C=C1CC(OC(C)OCC)C2OC(C)(C)OC2C1CO[Si](C)(C)C(C)(C)C
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOC(C)OC1CC(=C(C)O)C(CO[Si](C)(C)C(C)(C)C)C2OC(C)(C)OC12
Reaction time: 3 h

Procedure:
Two grams of ethyl (2-(tert-butyldimethylsilyloxymethyl)-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy) cyclohexylidene)acetate were dissolved in 10 ml of dry toluene, and 4.7 ml of diisobutyl aluminum hydride (2N hexane solution, 9.4 mmol) was added at -78° C., followed by stirring the mixture for 3 hours. After stirring at 0° C. for 5 minutes, a 10% sulfuric acid aqueous solution was added gradually until the reaction mixture became white. The reaction mixture was extracted with diethyl ether. The extract was washed with a sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate, and concentration was effected under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.47 g of (2-(tert-butyldimethylsilyloxymethyl)-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy)cyclohexylidene) ethanol having the following properties.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:16]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15]>C(Cl)Cl>[CH2:11]([C:16]1([CH:22]=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC1(CO)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCC1(C=O)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
DMSO (930 L) was added to a −78° C. solution of oxalyl chloride (3.2 mL, 2 M/toluene) in CH2Cl2 (44 mL). After 15 min., a solution of alcohol 2-3 (968 mg, 5.3 mmol) in 14 mL CH2Cl2 was added by cannula, rinsing with 2 mL CH2Cl2. The reaction was stirred for 15 min. and Et3N (5.9 mL) was added. The reaction was allowed to warm to 0° C. and after 2 h, 100 mL saturated NaHCO3 solution was added. The resulting mixture was extracted with CH2Cl2 (3×) and the combined CH2Cl2 solution was washed with H2O and brine and then was dried (Na2SO4), filtered and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:22]=2[CH3:23])=[O:17])[CH2:10][CH2:11][CH2:12][CH:13]=C)[CH:6]=[CH:7][CH:8]=1.[O:33]=[O+][O-]>C(Cl)Cl>[O:33]=[CH:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:22]=1[CH3:23])=[O:17])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:32])([F:31])[F:1])[CH:4]=1
Reactant: C=CCCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cccc(C(F)(F)F)c1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: Cc1c(C(=O)N[C@@H](CCCC=O)c2cccc(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Temperature: -78 °C

Procedure:
A solution of 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-hex-5-enyl]-amide (800 mg, 1.7 mmol) in CH2Cl2 (25 mL) at −78° C. is treated with ozone gas by bubbling for 30 min until a blue color is sustained. After stirring for an additional hour at −78° C., dimethylsulfide (10 mL) is added. The reaction mixture is warmed to room temperature and concentrated in vacuo to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-5-oxo-1-(3-trifluoromethyl-phenyl)-pentyl]-amide which is used without further purification.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:22][C:23]([S@@:26]([NH2:28])=[O:27])([CH3:25])[CH3:24]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:22][C:23]([S@@:26](/[N:28]=[CH:20]/[C:18]1[N:19]=[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:15]2=[N:16][CH:17]=1)=[O:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=N/[S@@](=O)C(C)(C)C)cnc32)cc1
Reaction time: 20 h
Yield: 99.1 %

Procedure:
To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (8.66 g, 28.7 mmol, Preparation #12 Step B) and (S)-2-methylpropane-2-sulfinamide (4.18 g, 34.5 mmol) in DCM (20 mL) at ambient temperature was added anhydrous powdered copper(II) sulfate (13.8 g, 86 mmol). After about 20 h, the reaction mixture was filtered and partially concd in vacuo. Heptane was added to the solution and the resulting solids were collected by filtration and dried in vacuo to provide (S,E)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylene)propane-2-sulfinamide (11.5 g, 99%) as a solid. LC/MS (Table 1, Method a) Rt=2.50 min; MS m/z: 405 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>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.COCCOC>[C:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
2-Chloro-5-nitropyridine (3.0 g, 18.9 mmol), phenylboronic acid (2.5 g, 20.8 mmol), and tetrakis(triphenylphosphine)palladium (0.2 g, 0.2 mmol) were added to 1,2-dimethoxyethan (30 ml), then degassed and purged with nitrogen three times under reduced pressure. Under nitrogen atmosphere the mixture was stirred at room temperature for 20 minutes, then 1M aqueous sodium carbonate (40 ml) was poured in, and the temperature was raised to 80° C. After the reaction at 80° C. for 6 hours, the mixture was cooled to room temperature and crystallized with addition of water. The precipitated crystals were filtered to give the title compound (3.7 g, 96.8%).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:23]([CH2:24][CH2:25][C:26]4[N:30]=[CH:29][NH:28][CH:27]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCCc1c[nH]cn1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(CCc1c[nH]cn1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with histamine (0.16 g, 1.4 mmol). Purification using silica gel, eluting with 9:1 CH2Cl2 /MeOH, afforded a solid that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 118 as a white solid (m.p. 190-191° C.).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13]3[N:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)(=O)=O.[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CI>O1CCOCC1>[CH3:21][S:2][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13]3[N:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[C:9]=2[CH:20]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1Nc2cccnc2Nc2ccc(S(=O)(=O)Cl)cc21
Solvent: C1COCCO1
Solvent: CI
Product: CSc1ccc2c(c1)C(=O)Nc1cccnc1N2

Procedure:
Intermediate 7, freshly prepared from 6 (0.5 g, 2.4 mmol) , was reduced with triphenylphosphine (2.8 g, 11.0 mmol) in dioxane (20 mL) for 2 h at 90° C. See Oae, S.; Togo, H., Bull. Chem. Soc. Jpn., 1983, 56, 3802, which is specifically incorporated by reference herein. The crude 8-thio-derivative was quenched (10 min, 25° C.) with excess methyl iodide (0.5 mL, 8.0 mmol) and crystallized from toluene to yield 50 mg (8% from 6) of 8 as a waxy solid: 1H NMR (CDCl3) δ 2.40 (s, 3 H, CH3), 6.25 (br s, 1 H, NH), 6.66 (d, J=8.3, 1 H), 6.86 (dd, J=7.7, 4.4 Hz, 1 H), 7.06 (d, J=8.2 Hz, 1 H), 7.24 (dd, J= 8.3, 2.3 Hz, 1 H), 7.79 (d, 13 J=2.3 Hz, 1 H), 7.91 (d, J=4.5 Hz, 1 H); MS (CI/NH3) m/e 258 (MH+, base), 243,211, 113.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24]Br>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Fc1cc(F)cc(CBr)c1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(F)cc(F)c2)c(=O)[nH]c1=O
Yield: 50.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (195 mg, yield: 50.5%).