Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[H][H].O.C>C(OCC)(=O)C.[Pd].Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)=[CH:19][CH:18]=2)([C:13]([F:14])([F:15])[F:16])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Nc1ccc(C(c2ccc(Oc3cccc([N+](=O)[O-])c3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(C(c2ccc(Oc3cccc(N)c3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 20 °C

Procedure:
22.8 g (0.05 mol) of 2-(4-aminophenyl)-2-[4-(3-nitrophenoxy)phenyl]hexafluoropropane were dissolved in 600 cm3 of ethyl acetate, 1 g of palladium on charcoal was added, and the mixture was reduced in a 1 dm3 steel autoclave at about 25° C. using hydrogen (100 bar). When the take-up of hydrogen was complete, the catalyst was filtered off and all the ethyl acetate was removed. The oily, brown crude product was chromatographed over basic alumina using ethyl acetate as eluent. The principal fraction was evaporated to dryness, giving 18 g of a highly viscous, pale yellow residue. 9.5 g of the pale yellow residue were suspended in 100 cm3 of hydrochloric acid (1:1), and 400 cm3 of water were added at the boiling point. The turbid solution was treated twice at the boiling point with 5 g of activated charcoal in each case. The clear, colorless solution was cooled to 20° C., a white solid precipitating out. The suspension was adjusted to a pH of 8-9 under a protective gas (nitrogen) using dilute ammonia solution. The solid was, under a protective gas, filtered off, washed with water and dried.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[C:16]([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[C:17]=1[C:18]([O:20]C)=[O:19])[C:11]1[O:12][CH2:13][O:14][C:10]=1[CH:9]=[CH:8]2)=[O:4].[OH-].[K+].COC(C1C(C2C=CC3OCOC=3C=2)=C2C(C=CC3OCOC=32)=CC=1C(O)=O)=O>CO>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:16]3[C:17]([C:18]([OH:20])=[O:19])=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]4[C:15]=3[C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=[CH:8]4)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: COC(=O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1C(=O)OC)OCO3
Agent: COC(=O)c1c(C(=O)O)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1C(=O)O)OCO3
Yield: 63.1 %

Procedure:
Compound 30 (20 mg, 0.05 mmol) was refluxed with 1 M solution of KOH in MeOH (10 mL) for 24 h. Completion of the reaction, followed by the workup as described for the isolation of 31, gave a residue, which was purified by silica gel column chromatography. Elution with CH2Cl2/MeOH (2:1, v/v) as eluent yielded 32 (12 mg, 63%) as a yellow powder. mp 253° C. (decomp.); 1H NMR (DMSO-d6) δ 8.25 (s, 1H, H4), 7.53 (d, 1H, H5, J=8.7 Hz), 7.24 (d, 1H, H6, J=8.7 Hz), 6.72-6.82 (m, 3H, H2′+H5′+H6′), 5.99 (AB, 2H, 3′,4′-OCH2O—, Δδ=18.9 Hz), 5.81 (AB, 2H, 7,8-OCH2O—, Δδ=6.0 Hz); MS (FAB, positive) m/z 381 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O>CC#N>[Cl:11][C:10]1[C:2](=[O:1])[NH:3][CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=C(O)c1c[nH]c(=O)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 6-hydroxy nicotinic acid (0.500 g, 3.59 mmol, TCI) in MeCN (20 mL), was added N-chlorosuccinimide (0.436 mL, 5.39 mmol, Aldrich). The resulting mixture was then heated at 80° C. for 72 h. A white precipitate was present. The mixture was filtered and the white solid was washed with EtOAc (2×1 mL) and dried in vacuo to afford the title compound as a white solid. MS (ESI, positive ion) m/z: 174,176 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][OH:22])[CH:18]=2)[NH:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][O:22][S:32]([CH3:31])(=[O:34])=[O:33])[CH:18]=2)[NH:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(CCO)cc2c1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a mixture of 5-(2-hydroxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.02 g, 3.3 mmol) and triethylamine (0.92 mL, 6.6 mmol) in dry THF (10 mL) was added methanesulfonyl chloride (0.26 mL, 3.3 mmol) under nitrogen atmosphere at room temperature. The mixture was stirred at room temperature for 3 hours and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 1.27 g (99%) of the desired product as a white solid: mp 122-124° C.; MS(APCI−): m/z 386.0 (M−H); Anal. Calcd for C20H21N1O5S1: C, 62.00; H, 5.46; N, 3.62; S, 8.28. Found: C, 61.95; H, 5.61; N, 3.54; S, 8.32.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([NH:27][CH:28]1[C:54](=[O:55])[N:30]2[C:31]([C:51]([OH:53])=[O:52])=[C:32]([CH2:35][S:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43](=[O:50])[N:44]([CH2:46][C:47]([OH:49])=[O:48])[N:45]=4)[N:42]=3)[CH2:33][S:34][C@H:29]12)=[O:26])C)=O)CCC>CCOCC>[CH3:13][NH:15][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([NH:27][CH:28]1[C:54](=[O:55])[N:30]2[C:31]([C:51]([OH:53])=[O:52])=[C:32]([CH2:35][S:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43](=[O:50])[N:44]([CH2:46][C:47]([OH:49])=[O:48])[N:45]=4)[N:42]=3)[CH2:33][S:34][C@H:29]12)=[O:26]
Reactant: CCCCOC(=O)N(C)Cc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nn(CC(=O)O)c(=O)n4n3)CS[C@H]12
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nn(CC(=O)O)c(=O)n4n3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Trifluoroacetic acid (7 ml.) was added to the t-BOC-derivative 7b (3.8 g., 5.5 m.mole) at 0° C., and the mixture was stirred for 20 minutes at room temperature. Dry ether (100 ml.) was added to the mixture. The resulting precipitate was collected by filtration and washed with dry ether (3 × 100 ml.). The precipitate was dissolved in a mixture of CH3CN (120 ml.) and water (18 ml.) and the solution was adjusted to pH 5-6 with concentrated NH4OH to give an oily precipitate which was triturated with CH3CN to form solid material. The product 8b was collected by filtration, washed with CH3CN and dried. Yield 2.55 g. (77%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11])=[O:7].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23]>O1CCCC1>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[O:3][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6](=[O:7])[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1ccccc1C(=O)c1ccccc1O
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=S)Oc1ccccc1C(=O)c1ccccc1C#N
Temperature: 50 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
1 g (0.041 mol) of sodium hydride is added in small amounts to a solution of 6.7 g (0.030 mol) of the 2-(2-hydroxybenzoyl)benzonitrile obtained in Preparation VIIIc in 200 ml of tetrahydrofuran. The mixture obtained is stirred for 1 hour at 50° C. The reaction medium is cooled to room temperature and a solution of 4.6 g (0.037 mol) of dimethylthiocarbamoyl chloride in 50 ml of tetrahydrofuran is added. The mixture obtained is stirred for 3 hours at room temperature and then hydrolyzed with an ice/water mixture. Extraction is carried out with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. 6 g of the expected product (yield: 64.5%) are obtained after crystallization from ether.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:65][C:66]1[S:67][C:68]2[CH:74]=[CH:73][CH:72]=[CH:71][C:69]=2[N:70]=1>>[S:67]1[C:68]2[CH:74]=[CH:73][CH:72]=[CH:71][C:69]=2[N:70]=[C:66]1[S:65][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1
Reactant: Sc1nc2ccccc2s1
Reactant: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCSc3nc4ccccc4s3)CC2)c(N2CCCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzothiazole, to thereby yield the title compound as a pale yellow solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[NH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1>ClCCl>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[NH:7][C:18]1([C:5]#[N:6])[CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc2ccccc2c1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCC1
Solvent: ClCCl
Product: N#CC1(Nc2ccc3ccccc3c2)CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
Trimethylsilyl cyanide (0.27 ml, 2 mmol) was added dropwise to a mixture of 2-aminonaphthalene (0.143 g, 1 mmol) and cyclobutanone (0.098 g, 1.4 mmol). The reaction mixture was stirred at room temperature for 12 h and then concentrated under vacuum to obtain a brown liquid which was subjected to chromatography (dichloromethane) to yield 13a (0.209 g, 0.94 mmol, 94%) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Cl:16])=[CH:9][C:4]=1[C:5](OC)=[O:6].C[CH2:18][N:19](CC)CC.CN.CCO.Cl>CO.CCOC(C)=O>[Cl:16][C:10]1[CH:9]=[C:4]2[C:3]([CH2:2][N:19]([CH3:18])[C:5]2=[O:6])=[CH:12][C:11]=1[N+:13]([O-:15])=[O:14]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1CBr
Agent: CN
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1Cc2cc([N+](=O)[O-])c(Cl)cc2C1=O
Temperature: 70 °C
Yield: 76.6 %

Procedure:
To methyl 2-(bromomethyl)-5-chloro-4-nitrobenzoate (617 mg, 2 mmol) in methanol (18 mL) was added Et3N (0.34 mL, 2.4 mmol) and methylamine in EtOH (0.3 mL, ˜d 8 M in EtOH, 2.4 mmol). The mixture was heated to 70° C. for 3 h. and then EtOAc (30 mL) and 2M HCl(aq) (30 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic fractions were passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-10% methanol in DCM) gave 6-chloro-2-methyl-5-nitroisoindolin-1-one (347 mg, 77%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=227 at 2.89 min. 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.90 (s, 1H), 4.46 (s, 2H), 3.24 (s, 3H).
Reaction SMILES: [OH-].[K+].[CH2:3]1[C:16]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[C:6](=[O:17])[CH2:5][CH2:4]1.[CH3:18][C:19]1[N:23]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[N:21][C:20]=1[CH:43]=O>CO>[CH3:18][C:19]1[N:23]([C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:22]=[N:21][C:20]=1[CH:43]=[C:5]1[C:6](=[O:17])[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:16]=2[CH2:3][CH2:4]1
Reactant: O=C1CCCc2ccc3ccccc3c21
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C=C2CCc3ccc4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 120 h
Yield: 63.6 %

Procedure:
A solution of potassium hydroxide (0.25 g) in methanol (5 ml) was added to a solution of 1,2-dihydro-4(3H)-phenanthrenone (0.5 g) and 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (0.9 g) in methanol (20 ml). The mixture was kept at 23° for 5 days after which time a solid had separated. This was filtered off, washed with ethanol and purified by FCC eluting firstly with hexane/dichloromethane (1:1) and then with dichloromethane to give the title compound (0.86 g), m.p. 145°-148° (decomp.).
Reaction SMILES: O.O.O.[Br:4]([O-])(=O)=O.[Na+].[Cl:9][C:10]1[C:18]2[O:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][C:14]=2[CH:13]=[C:12]([C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[O:25])[C:11]=1[Cl:32]>O.C(O)(=O)C>[Cl:9][C:10]1[C:18]2[O:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][C:14]=2[CH:13]=[C:12]([C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[Br:4])=[O:25])[C:11]=1[Cl:32]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CCOC(=O)C1Oc2cc(C(=O)c3ccnn3C)c(Cl)c(Cl)c2O1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1Oc2cc(C(=O)c3c(Br)cnn3C)c(Cl)c(Cl)c2O1
Reaction time: 15 h
Yield: 41.2 %

Procedure:
A solution of 1.53 g of sodium bromate trihydrate in 5 ml of water is added to a solution of 2.0 g of ethyl 4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodi oxole-2-carboxylate in 20 ml of acetic acid at room temperature. The mixture is stirred at the same temperature for 15 hours. The reaction mixture is concentrated under reduced pressure to remove acetic acid. The residue is neutralized by addition of an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane-ethyl acetate) to give 1.0 g of ethyl 4,5-dichloro-6-(1-methyl-4-bromo-5-pyrazolylcarbonyl)-1,3-benzodioxol e-2-carboxylate as an oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=O)[CH3:2].[C:8]([CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])#[N:9].C(O)(=O)C.N1CCCCC1>>[CH2:14]([O:13][C:11](=[O:12])[C:10]([C:8]#[N:9])=[CH:4][CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCC(C=O)CC
Reactant: N#CCC(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCC(C=C(C#N)C(=O)OCc1ccccc1)CC
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a mixture of 2-ethylbutyraldehyde (2.0 mL, 16.2 mmol) and benzyl cyanoacetate (2.85 g, 16.2 mmol) at 0° C. was added acetic acid (0.1 mL, 1.62 mmol), then piperidine (0.16 mL, 1.62 mmol) dropwise. The ice bath was removed, and stirring continued for 10 minutes. Additional acetic acid (0.1 mL) and piperidine (0.16 mL) were added, followed by the additional of oven-dried 4A molecular sieves such that stirring was not impeded. The mixture was stirred 1.5 h, then partitioned between EtOAc and sat. NaHCO3 (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide 3.96 g (95%) of 2-cyano-4-ethyl-hex-2-enoic acid benzyl ester as a colorless oil. 1H NMR (CDCl3) δ 7.39 (m, 6H), 5.28 (s, 2H), 2.60 (m, 1H), 1.62 (m, 2H), 1.40 (m, 2H), 0.88 (t, J=7.6 Hz, 6H). 13C NMR δ 168.69, 161.40, 135.01, 128.90, 128.82, 128.50, 114.11, 109.94, 68.07, 46.35, 27.30, 11.95. IR (neat) 2233, 1729 cm−1. LRMS: m/z 256.1 (M−1). Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.75; H, 7.52; N, 5.50.
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH2:31][C@H:32]([CH2:40][OH:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([C@H:32]([NH:31][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH2:40][OH:41])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: N[C@H](CO)Cc1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (S)-phenylalaninol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.13 (1H, s) 7.98 (1H, d, J=5.47 Hz) 7.72-7.82 (2H, m) 7.40 (1H, d, J=5.42 Hz) 7.28 (1H, dd, J=3.44, 2.32 Hz) 7.19 (4H, d, J=0.10 Hz) 7.10 (1H, td, J=5.93, 2.59 Hz) 6.73 (1H, d, J=5.52 Hz) 6.38 (1H, dd, J=3.42, 1.76 Hz) 4.82 (1H, t, J=5.66 Hz) 4.13 (1H, ddd, J=14.19, 5.60, 3.15 Hz) 3.42-3.51 (1H, m) 3.38 (1H, t, J=5.93 Hz) 2.84-2.93 (1H, m) 2.73 (1H, dd, J=13.64, 8.96 Hz)
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.FC(F)(F)C(O)=O.[NH:30]1[CH2:33][CH:32]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:31]1>>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][CH:32]1[CH2:33][N:30]([C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: c1ccc(CC2CNC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CC2CN(c3c4c(nc5ccnn35)CCNCC4)C2)nc1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-azetidin-3-ylmethyl-pyridine trifluoroacetate was used as the amine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:24])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CC1CC(C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)C1
Product: CC1CC(C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)Cl)c2)C1

Procedure:
2-Chloro-5-(3,5-dimethylpiperidinosulfonyl)benzoic acid (6.0 g.) is refluxed for 21/2 hours with 50 ml. of thionyl chloride, and then taken to dryness. The residue is triturated with 200 ml. of hot benzene-hexane (1:1), filtered and evaporated to obtain the dry product, m.p. 164°-166.5° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)(=O)=O.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CN1C(=O)CCC1>O>[CH3:18][N:8]([CH2:7][CH2:6][N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: CN(CCOS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCN(CCN(C)c2cccc([N+](=O)[O-])c2)CC1

Procedure:
A mixture of 2-[methyl(3-nitrophenyl)amino]ethyl methanesulfonate (Preparation Example 472) (1.0 g), 1-methylpiperazine (1.61 mL) and NMP (5 mL) was reacted at 130° C. for 30 minutes using a microwave reaction system. The reaction liquid was diluted with water, extracted with a mixed solvent of chloroform and methanol (10:1), and then washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=10:1:0.1) to give N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-3-nitroaniline (890 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:6]([CH:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[N:7]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[N:6]([C:8]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[C:9]([CH:11]=[O:12])[N:10]=2)[N:7]=1
Reactant: O=Cc1cn2nc(Cl)cc(N3CCOCC3)c2n1
Reactant: Brc1cccnc1
Product: O=Cc1nc2c(N3CCOCC3)cc(Cl)nn2c1-c1cccnc1

Procedure:
Compound 73e was a coupled with 3-bromopyridine (0.100 mL, 1.25 mmol) according to the procedures described in Example 20, Step A to afford compound 73f. Mass Spectrum (LCMS, ESI pos.): Calcd. for C16H14ClN5O2: 344.0 (M+H). found: 344.0.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7](OC)[C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([O:19][CH3:20])[CH:4]=1)=[O:2].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:30](=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=[CH:7][C:6]=1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:30])[CH:22]=1
Reactant: COc1cc(C=O)cc(OC)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C=O)ccc1-c1cccc(C)c1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
The triflate 3 was dissolved in toluene followed by the addition of phenyl boronic acid, tetrakis(triphenylphosphine)Pd, potassium carbonate and water in a microwave tube equipped with a stir bar. The tube was sealed and the reaction was carried out in a microwave synthesizer for 15 mins at 120° C. and 100 watts. After the completion of the reaction the reaction mixture was dissolved in DCM washed with sodium bicarbonate, water and brine. The product was isolated as clear viscous oil using 10% EtOAc/hexanes as the solvent system. Yield=73.0% (Rf=0.27; 10% EtOAc/hexanes), 1H NMR, 500 MHz Varian, CDCl3, δ10.01 (s, 1H), 7.53 (d, J=15.00 Hz, 1H), 7.51 (d, J=15.00 Hz, 1H), 7.49 (d, J=10.00 Hz, 1H), 7.34 (s, 3H), 7.21 (d, J=7.0, 1H), 3.89 (s, 3H), 2.41 s, 3H), MS: m/z (ESI, pos.)=249.2 ([M+23])
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[C:12]([NH2:15])(=[O:14])[CH3:13].[CH2:16]=O>S(=O)(=O)(O)O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][C:8]=1[CH2:16][NH:15][C:12](=[O:14])[CH3:13])[CH3:2]
Reactant: CCc1ccc([N+](=O)[O-])cc1
Reactant: CC(N)=O
Reactant: C=O
Agent: O=S(=O)(O)O
Product: CCc1ccc([N+](=O)[O-])cc1CNC(C)=O
Temperature: 55 °C
Reaction time: 17 h
Yield: 56 %

Procedure:
4-Ethylnitrobenzene (7.55 g; 0.05 mol) is added in small increments to a stirred solution of acetamide (5.9 g; 0.05 mol) and paraformaldehyde (1.6 g; 0.05 mol) in concentrated sulfuric acid (60 ml). This reaction mixture is stirred for 17 hours at 55° C. and then poured onto ice. A precipitate results which is recrystallized from butyl acetate to give 6.2 g (i.e., 56% yield) of product. This product has the following characteristics: melting point of 123° to 128° C.; i.r. 3275, 1640 and 1660 cm-1 (sh); mass. spec. m/e 222.