Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:33][CH2:32][CH2:31][C@:3]1([CH3:34])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:27]([CH3:30])[CH2:28][CH3:29])[C@H:16]([O:25][CH3:26])[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[CH2:33][CH2:32][CH2:31][C@:3]1([CH3:34])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:27]([CH3:30])[CH2:28][CH3:29])[C@H:16]([O:25][CH3:26])[CH2:17][C:18]([OH:20])=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Yield: 109.4 %

Procedure:
According to the general procedure B, from #195 (11.1 g, 21.6 mmol, 1 eq.), dichloromethane (100 mL) and trifluoroacetic acid (40 mL) was synthesized the crude desired material, to obtain #196 (10.1 g, quantitative yield) which was used in the next step without further purification. LC-MS (Protocol Z): m/z 428.5 [M+H+], retention time=0.9 minutes.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>O1CCCC1>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:40](=[O:41])[C:39]3[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=3)[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccc([N+](=O)[O-])cc3)CC2)n1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
0.91 g of 4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]-butylamine (2.64 mmol) and 0.53 g of triethylamine (5.28 mmol) were dissolved in 20 ml of tetrahydrofuran. 0.49 g of 4-nitro-benzoyl-chloride (2.64 mmol) were added at 0-5° C. After stirring for 2 h at 0-5° C., the solvent was evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (2%). Fractions containing the product were combined. The solvent was evaporated to yield 0.51 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20].O>ClCCl.C(OCC)(=O)C>[Cl:17][CH:18]([Cl:22])[C:19]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C#Cc1cncc(N)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1cncc(NC(=O)C(Cl)Cl)c1
Yield: 66.1 %

Procedure:
A mixture of 3-amino-5-ethynylpyridine (20.73 g, 23.1 mmol) and triethylamine (3.54 mL, 25.42 mmol) in dichloromethane was cooled in an ice bath. A solution of dichloroacetyl chloride (2.57 mL, 25.42 mmol) in dichloromethane was added dropwise. After stirring for one more hour, water and ethyl acetate were added. The organic layer was separated, washed with saturated sodium hydrogen carbonate, dried over sodium sulfate, filtered and concentrated in vacuo to yield 3-(2,2-dichloroacetamido)-5-ethynylpyridine (3.5 g).
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=[O:7].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[C:17]([OH:35])[C:16]=1[O:36][CH3:37].C([Sn](=O)CCCC)CCC>CO>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][CH2:27]2)=[C:17]([OH:35])[C:16]=1[O:36][CH3:37].[C:1]([O-:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7]
Reactant: COC(=O)CCCCC(=O)OC
Agent: CCCC[Sn](=O)CCCC
Agent: COc1ccc(CN2CCN(Cc3ccccc3)CC2)c(O)c1OC
Solvent: CO
Product: O=C([O-])CCCCC(=O)[O-]
Temperature: 180 °C

Procedure:
Into the resin cook apparatus described in Example 1 are charged dimethyl adipate (200 grams, 1.15 moles), BHDP (302 grams, 1.37 moles), and dibutyltin oxide (1.0 gram). The mixture is heated at 180° C. for 4 hours. A conversion of 93 percent is obtained based upon the methanol taken overhead. The tacky polyester has an average molecular weight of 1.974, an acid number of 2.4, and a hydroxyl number of 50.0.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21](=[O:24])[NH:22][NH2:23])([CH3:19])([CH3:18])[CH3:17].C([BH3-])#N.[Na+]>C1COCC1>[C:10]([CH:9]([NH:23][NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:24])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCc1ccccc1)NNC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of ethyl 4-phenyl-2-oxobutanoate (2.06 g; 10 mmol) and t-butylcarbazate (1.32 g; 10 mmol) in THF (50 ml) can be warmed at reflux for 8 hours. Solvent can be evaporated and the residue taken up in anhydrous ethanol (25 ml). Sodium cyanoborohydride (0.31 g; 5 mmol) can be added, and the solution stirred for 4 hrs. The residue, after evaporation, can be stirred with EtOAc (50 ml) and hydrochloric acid (0.5 N: 20 ml) for 30 minutes. The aqueous layer can be neutralized by addition of K2CO3 and extracted with EtOAc (3×25 ml). The combined organic portions can be washed with H2O and brine and dried (MgSO4). The residue, upon evaporation, can be purified by chromatography on silica gel, affording N-(1-carboethoxy-3-phenylpropyl)-N'-BOC-hydrazine. An ice-cold solution of the above hydrazine in trifluoroacetic acid can be allowed to stand for 1 hr. Removal of solvent can provide hydrazine (56) as the trifluoroacetic acid salt.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:13]=[CH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=2.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:13]2[N:4]3[C:5]4[C:10]([N:11]=[CH:2][C:3]3=[N:15][CH:14]=2)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=4)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Clc1ccc2nc(Cl)c3nccn3c2c1
Reactant: NC1CCCCC1
Product: Clc1ccc2ncc3ncc(NC4CCCCC4)n3c2c1

Procedure:
By reaction of 4,8-dichloroimidazo[1,2-a]quinoxaline (example 18) with cyclohexylamine, following a procedure that is similar to that described in example 3, there is obtained 4-(1-cyclohexylamino-8-chloroimidazo[1,2-a]quinoxaline. m.p. (DSC)=126.7° C.(onset); IR (KBr): 3413, 2926, 1555 cm-1 ; 1H-NMR (CDCl3): δ7.85 (1H,s), 7.7÷7.2 (4H,m), 6.1 (1H,d), 4.2 (1H,m), 2.3÷2.0 (4H,m), 2.0÷1.2 (6H,m); UV (EtOH): λmax =229, 245, 289, 301, 326, 340 nm. Elementary analysis for C16H17ClN4 (m.w. 300.79): calcd. C 63.89, H 5.70, N 18.63%; found C 64.07, H 5.79, N 18.80%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:14][CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2C(O)=O)[CH:7]=1.CS(C)=O.C(O)(C(F)(F)F)=O>CN(C=O)C.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH3:15])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1
Reactant: COc1nc(Cl)cn2ncc(C(=O)O)c12
Agent: [Pd+2]
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1nc(Cl)cn2nccc12
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
Crude 6-chloro-4-methoxypyrazolo[1,5-a]pyrazine-3-carboxylic acid from above (611 mg, 2.68 mmol) was dissolved along with palladium(II) trifluoroacetate (401 mg, 1.2 mmol) in DMF (24 mL). DMSO (1.6 mL) and TFA (2 mL, 26 mmol) were added and the resulting mixture was heated to 110° C. After stirring 2.5 h, the reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo and was partitioned between EtOAc, saturated aqueous NaHCO3 and water. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water and was dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel (5-30% EtOAc in hexanes) to provide 6-chloro-4-methoxypyrazolo[1,5-a]pyrazine 5.36. LCMS-ESI+ (m/z): [M+H]+ calcd for C7H7ClN3O: 184.0; found: 184.2.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([S:15][C:16]2[CH:17]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([F:22])[CH:21]=2)[CH:10]=[CH:11][C:12]=1[CH2:13]Cl>>[Cl:6][C:7]1[CH:8]=[C:9]([S:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)[CH:10]=[CH:11][C:12]=1[CH2:13][O:5][N:4]=[C:2]([CH3:3])[CH3:1]
Reactant: CC(C)=NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(CCl)c(Cl)c3)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc(CON=C(C)C)c(Cl)c3)c2)CCOCC1
Yield: 50 %

Procedure:
Using an analogous procedure to that described in Example 1, acetone oxime was reacted with 4-[3-(3-chloro-4-chloromethylphenylthio)-5-fluorophenyl]-4-methoxytetrahydropyran to give acetone O-{2-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzyl}oxime as a gum in 50% yield.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]#[CH:8])[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].O.[Cl:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23].Cl.[Na+].[Cl-]>O.O1CCOCC1.CCOC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH:1][C@H:2]([CH2:6][C:7]#[CH:8])[C:3]([OH:5])=[O:4])(=[O:25])=[O:26])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: C#CC[C@@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C#CC[C@@H](NS(=O)(=O)c1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
(R)-2-Aminopent-4-ynoic acid (16.0 g, 141 mmol) and Na2CO3.H2O (36.8 g, 296 mmol) were dissolved in 500 mL H2O and 300 mL p-dioxane. To this solution was added 3,4-dichlorobenzene-1-sulfonyl chloride (33.0 g, 134 mmol) dropwise over 25 min. The solution was stirred at RT for 19 h. The solution was then acidified with 5N HCl to pH 1. EtOAc (400 mL) and sat'd NaCl aq. (200 mL) were added and organic layer was separated. The aqueous phase was extracted with EtOAc (200 mL×2), and the combined EtOAc extracts were washed with brine (400 mL×4) and dried over Na2SO4. The solvent was removed under reduced pressure and dried in vacuo to yield 38.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][N:10]2[CH2:15][C:14]3[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:18]=[N:19][C:13]=3[NH:12][C:11]2=[O:25])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:45][NH:46][CH2:47][C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51]([CH3:58])=[CH:50][CH:49]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH3:45][N:46]([CH2:47][C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51]([CH3:58])=[CH:50][CH:49]=1)[C:22](=[O:23])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[N:19][C:13]2[NH:12][C:11](=[O:25])[N:10]([CH2:9][CH2:8][N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[CH2:15][C:14]=2[CH:16]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Reactant: CNCc1ccc(C)c2ccccc12
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1ccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)c2ccccc12
Yield: 50 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(4-methyl-naphthalen-1-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (175 mg, 50%) was prepared as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.50 (br s, 1H), 10.14-10.09 (m, 1H), 8.41-8.30 (m, 1H), 8.16-7.85 (m, 3H), 7.69-7.53 (m, 3H), 7.40-7.01 (m, 3H), 5.37-4.85 (m, 4H), 4.65-4.46 (m, 2H), 3.99-3.93 (m, 2H), 3.78-3.31 (m, 6H), 3.20-2.98 (m, 5H), 2.65-2.63 (m, 3H); MS (ESI) m/e 500 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21]I>C1COCC1>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCCc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a mixture of [3-(4-fluoro-phenyl)-propyl]-carbamic acid tert-butyl ester (0.390 g, 1.540 mmol) and NaH (0.092 g, 2.310 mmol, 60% in mineral oil) in 10 mL of THF, was added via a syringe MeI (0.19 mL, 3.080 mmol). After stirring overnight at room temperature under N2, the reaction was quenched with NH4Cl solution (40 mL) and the resulting mixture extracted with dichloromethane (40 mL×3). The combined organic extracts were dried, filtered, and concentrated under reduced pressure. The product was isolated using Flash column chromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (0.417 g, >99% yield). GC-MS: tR=8.6 min; m/z 267 (M+).
Reaction SMILES: C(OC([NH:8][C:9]([NH:25]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[CH3:24])=O)(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[ClH:33].[CH3:24][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)=[CH:16][C:11]=1[NH:10][C:9]([NH2:25])=[NH:8]
Reactant: Cc1ccnc(-c2ccc(C)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccnc(-c2ccc(C)c(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(2-methyl-5-(4-methylpyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 ml) and ethyl acetate (10 ml), and the precipitate was collected by filtration and dried under reduced pressure to give (2-methyl-5-(4-methylpyridin-2-yl)phenyl)guanidine dihydrochloride (127 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([OH:26])[CH3:25])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C@H:24]([OH:26])[CH3:25])=[CH:21][CH:22]=2)[CH:7]=1
Reactant: C[C@@H](O)Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Product: C[C@@H](O)Cc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and (2R)-1-(4-aminophenyl)-2-propanol (step 2 of Example 249).
Reaction SMILES: C([Li])CCC.[CH:6]([NH:9]C(C)C)(C)C.[C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[CH3:20])#[N:14].CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.O1CCCC1.O>[NH2:9][CH2:6][C:17]1[S:16][C:15]([C:13]#[N:14])=[C:19]([CH3:20])[CH:18]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1ccsc1C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CN)sc1C#N
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 93.3 %

Procedure:
112 ml (179 mmol) of a 1.6 molar solution of n-butyllithium in n-hexane were added in the course of 20 minutes to a solution, cooled to −78° C., of 25.1 ml (179 mmol) of diisopropylamine in 400 ml of tetrahydrofuran. The solution was allowed to reach −35° C. and was cooled again to −78° C., and a solution of 20.0 g (162 mmol) of 2-cyano-3-methylthiophene in 80 ml of tetrahydrofuran was slowly added dropwise at this temperature. The solution acquired a dark red color. Stirring was continued for 45 minutes, 63 ml (811 mmol) of dimethylformamide were slowly added dropwise and stirring was carried out for a further 30 minutes. For working up, a solution of 27 g of citric acid and 160 ml of water was added at −70° C. Evaporating down was carried out in a rotary evaporator, 540 ml of saturated sodium chloride solution were added and extraction was effected with three times 250 ml of diethyl ether. The combined organic extracts were dried over magnesium sulfate. After the drying agent had been filtered off, the solvent was distilled off under reduced pressure from a water jet pump and the residue was purified by column chromatography (mobile phase: 4/1 hexane/ethyl acetate). 23 g (94%) of the title compound were obtained.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[S:1]1[C:5]2=[CH:6][N+:7]([O-:18])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cc2ccsc2cn1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc2ccsc2c1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 18 g of thieno[2,3-c]pyridine in 300 ml of chloroform was added 33 g of 3-chloroperbenzoic acid portionwise with ice-cooling over a period of 1 hour, and the mixture was stirred for further 1 hour under the same conditions. The reaction mixture was diluted with 400 ml of chloroform, washed successively with water, a saturated sodium carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure to give 16.6 g of thieno[2,3-c]pyridine-N-oxide as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:14]2[NH:26][C:17]3=[N:18][CH:19]=[C:20]4[CH:24]=[N:23][N:22]([CH3:25])[C:21]4=[C:16]3[CH:15]=2)=[CH:3]1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29]>ClCCCl.CC(O)(C)C.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:12])=[CH:8][CH:9]=2)[C:4]([C:14]2[NH:26][C:17]3=[N:18][CH:19]=[C:20]4[CH:24]=[N:23][N:22]([CH3:25])[C:21]4=[C:16]3[CH:15]=2)=[CH:3]1
Reactant: Cn1cc(-c2cc3c(ncc4cnn(C)c43)[nH]2)c2cc(C(=O)O)ccc21
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: Cn1cc(-c2cc3c(ncc4cnn(C)c43)[nH]2)c2cc(C(=O)NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
1-Methyl-3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-5-carboxylic acid (0.047 g, 0.14 mmol, Example #AN.1), methanesulfonamide (0.039 g, 0.41 mmol) and EDC (0.065 g, 0.34 mmol) were combined in a mixture of DCE (1.31 mL) and t-BuOH (1.31 mL). DMAP (0.050 g, 0.41 mmol) was added and the mixture was stirred at rt for about 16 h. The mixture was purified by flash chromatography (12 g silica gel column, (6:3:1 CHCl3/MeOH/saturated NH4OH)/EtOAc 50-85%) to give 1-methyl-3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-N-(methylsulfonyl)-1H-indole-5-carboxamide (0.024 g, 42%): LC/MS (Table 2, Method a) Rt=1.55 min; MS m/z 423 (M+H)+. Syk IC50=A.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH:10]([C:14]([OH:16])=[O:15])[C:11]([OH:13])=[O:12].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>Br.C(OCC)C>[Br:1][C:10]([CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH3:3])([C:14]([OH:16])=[O:15])[C:11]([OH:13])=[O:12]
Reactant: COCCOCCC(C(=O)O)C(=O)O
Reactant: BrBr
Agent: Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COCCOCCC(Br)(C(=O)O)C(=O)O
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
HBr (4.1 M in acetic acid, two drops) and bromine (1.44 g, 9.01 mmol) was added to a stirred solution of [2-(2-methoxyethoxy)ethyl]malonic acid (Step 2) (1.75 g, 8.49 mmol) in diethyl ether. The reaction mixture was kept at ambient temperature for 20 minutes when most of the bromine colour had disappeared. Sodium pyrosulfite (5% in water) was added and the two phases were separated. The aqueous phase was extracted with diethyl ether two times. The organic extracts were combined and washed with water. The organic phase was dried over MgSO4 and concentrated in vacuo to give the title product as a colourless solid (1.91 g), 1H NMR (300 MHz, CDCl3) δ 6.91 (br s, 2H), 3.75 (t, 2H), 3.62 (m, 4H), 3.42 (s, 3H), 2.70 (t, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][I:26]>O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([P:6]([O:5][CH2:3][CH3:4])([O:8][CH2:9][CH3:10])=[O:7])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][I:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][I:26])[CH3:16]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: ICCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCCCCI)(CCCCCCCCI)P(=O)(OCC)OCC
Temperature: 25 °C
Yield: 41.9 %

Procedure:
0.96 g (0.02 mol) of sodium hydride was added to 40 ml of dry tetrahydrofuran, and to this solution was added dropwise under reflux a mixed solution of 1.34 g (6 mmol) of ethyl diethylphosphonoacetate and 11 g (0.03 mol) of 1,8-diiodooctane, and the solution was refluxed under heating for 4 hours. After distilling off tetrahydrofuran, the residue was cooled to room temperature, added with 1N hydrochloric acid until the litmus paper came to show acidity of the solution and then extracted three times with 50 ml of ether. After drying the extract over anhydrous sodium sulfate, ether was distilled off and the obtained oily residue was refined by passing through a basic alumina(activity II)-packed column using benzene-ethyl acetate (2:1) as eluent to obtain 1.76 g of 2,2-bis(8-iodooctyl)-diethylphosphonoacetic acid ethyl ester, ##STR35## (yield: 42%).