Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][S:4]([N:7]1[CH2:16][CH2:15][CH2:14][C@@H:8]1[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])(=[O:6])=[O:5].[CH2:17]([S:24][C:25]1[N:30]=[C:29](NS(C)(=O)=O)[CH:28]=[C:27](NCCO)[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[ClH:40]>CN(C=O)C>[CH2:17]([S:24][C:25]1[N:30]=[C:29]([NH:3][S:4]([N:7]2[CH2:16][CH2:15][CH2:14][C@@H:8]2[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])(=[O:6])=[O:5])[CH:28]=[C:27]([Cl:40])[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cl
Reactant: CS(=O)(=O)Nc1cc(NCCO)nc(SCc2ccccc2)n1
Reactant: CN(C)C(=O)[C@H]1CCCN1S(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H]1CCCN1S(=O)(=O)Nc1cc(Cl)nc(SCc2ccccc2)n1
Reaction time: 1 h

Procedure:
60% Sodium hydride (0.42 g) was added to a solution of the subtitle product of step iii) (1.50 g) in DMF (20 ml) at 0° C. This mixture was stirred for 1 h and then a solution of the subtitle product of Example 19 step (1.60 g) in DMF (5 ml) was added dropwise. The mixture was allowed to reach room temperature and stirred there for 2 days. To the mixture was added aqueous hydrochloric acid (100 ml) and the resulting precipitate was filtered. This solid was then stirred with EtOAc (200 ml) and filtered to afford the subtitle compound as a solid. Yield: 2.0 g.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:10]1=[O:28].Cl[C:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].[NH:42]1[CH2:47][CH2:46][CH:45]([N:48]2[CH2:52][C:51](=[O:53])[NH:50][C:49]2=[O:54])[CH2:44][CH2:43]1>O1CCCC1>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:10](=[O:28])[C@H:9]([NH:8][C:30]([N:42]2[CH2:43][CH2:44][CH:45]([N:48]3[CH2:52][C:51](=[O:53])[NH:50][C:49]3=[O:54])[CH2:46][CH2:47]2)=[O:31])[CH2:15][CH2:14]1
Reactant: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reactant: O=C1CN(C2CCNCC2)C(=O)N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)N2CCC(N3CC(=O)NC3=O)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
Triethylamine (0.012 mL, 0.084 mmol) was added to a solution (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)azepan-2-one (25 mg, 0.084 mmol) and p-nitrophenyl chloroformate (25 mg, 0.126 mmol) in tetrahydrofuran (1 mL) at 0° C. After 0.5 h, triethylamine (0.036 mL, 0.252 mmol) and 1-piperidin-4-ylimidazolidine-2,4-dione (23 mg, 0.126 mmol) were added and the mixture was allowed to warm to ambient temperature. After 1 h, the mixture was quenched with water, extracted with ethyl acetate, and washed with 1 N NaOH solution. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0.5% methanol/dichloromethane→7% methanol/dichloromethane) gave the title compound (9 mg). MS 508.2 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([I:11])=[C:9]([C:12]([NH:14][CH2:15][CH:16]([O:22]C(=O)C)[CH2:17][O:18]C(=O)C)=[O:13])[C:8]([I:26])=[C:7]([CH2:27][O:28]C(=O)C)[C:6]=1[I:32])(=[O:3])[CH3:2].[OH-].[Na+].Br[CH2:36][CH:37]([OH:40])[CH2:38][OH:39].Cl>CO.O>[C:1]([N:4]([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[C:5]1[C:10]([I:11])=[C:9]([C:12]([NH:14][CH2:15][CH:16]([OH:22])[CH2:17][OH:18])=[O:13])[C:8]([I:26])=[C:7]([CH2:27][OH:28])[C:6]=1[I:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Reactant: OCC(O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N(CC(O)CO)c1c(I)c(CO)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 1 h

Procedure:
N-acetyl-3-acetoxymethyl-5-(2,3-diacetoxypropylaminocarbonyl)-2,4,6-triiodoaniline (1.0 g, 1.27 mmol) was suspended in a mixture of methanol (6 ml) and water (30 ml) and pH was adjusted to 12.0 using a 2M aqueous solution of NaOH. After stirring for 1 h, 1-bromo-2,3-propanediol (0.99 g, 6.4 mmol) was added and the pH was adjusted to 11.6 using a 2M aqueous solution of HCl. 1-Bromo-2,3-propanediol (0.99 g, 6.4 mmol) was again added after 16 and 18 h and after 24 h, pH was adjusted to 6.5 using a 2M aqueous solution of HCl. After evaporation, the residue was purified by preparative HPLC. Yield: 0.373 g (40%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:12])[CH:6]=[C:7]([O:9]C)[CH:8]=1.C(O)(=O)C.Br.[H][H]>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH3:12])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: [H][H]
Reactant: COc1cc(OC)cc(C(C)CCCc2ccc(F)cc2)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(CCCc1ccc(F)cc1)c1cc(O)cc(O)c1
Reaction time: 17 h

Procedure:
Fifty grams of the above-prepared 2-(3,5-dimethoxyphenyl)-5-(p-fluorophenyl)pentane, 450 ml. of acetic acid and 180 ml. of 48% HBr in water were mixed. While cooling, the mixture was saturated with hydrogen gas (approximately one-half hour). The reacion was placed in an 87° bath and stirred for 17 hours. The reaction was then concentrated in vacuo and the residue neutralized with K2CO3 and NaHCO3, extracted with ether, treated with charcoal and MgSO4 and filtered to yield 45 g. of 2-(3,5-dihydroxyphenyl)-5-(-p-fluorophenylpentane as a brown oil which distills at 180°/0.01 mmHg.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][C:10]1[C:15](O)=CC=C[CH:11]=1>>[C:10]([C:5]1[CH:4]=[CH:3][C:2]([CH3:8])=[CH:1][C:6]=1[OH:7])([CH3:15])([CH3:11])[CH3:9]
Reactant: Cc1ccccc1O
Reactant: Cc1cccc(O)c1
Product: Cc1ccc(C(C)(C)C)c(O)c1
Yield: 95 %

Procedure:
Run B of Example 1 is repeated except that 3-cresol is substituted for the cresylic acid mixture. The process results in a selectivity of better than 95 percent of 6-t-butyl-3-cresol.
Reaction SMILES: IC.[F:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:9]1.[C:32](=O)([O-])[O-].[Na+].[Na+]>C(O)C.O1CCCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][CH3:32])[CH:15]=2)[C:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:9]1
Reactant: Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCO
Product: CNc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Yield: 25 %

Procedure:
Iodomethane (0.568 ml, 9.12 mmol) was added to a solution of 1-(3,5-difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-1H-indol-6-ylamine (Example 15a; 2.5 g, 6.1 mmol) in a mixture of ethanol and tetrahydrofuran containing sodium carbonate (0.657 g, 6.08 mmol). The reaction mixture was heated under reflux overnight and concentrated. Water was added and the product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 8:2) afforded [1-(3,5-difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-1H-indol-6-yl]-methyl-amine (0.647 g) and [1-(3,5-difluoro-benzyl-3-(2-nitro-phenylsulfanyl)-1H-indol-6-yl]-dimethyl-amine (0.815 g). 1H-NMR (CDCl3) δ 8.26 (dd, 1H, J=8.2 and 1.2 Hz), 7.35 (d, 1H, J=8.6 Hz), 7.27 (ddd, 1H, J=8.2, 7.4 and 1.2 Hz), 7.25 (s, 1H), 7.17 (ddd, 1H, J=8.2, 7.4 and 1.2 Hz), 7.03 (dd, 1H, J=8.2 and 1.2 Hz), 6.78 (dd, 1H, J=8.6 and 2.3 Hz), 6.74 (tt, 1H, J=8.6 and 2.3 Hz), 6.68 (m, 2H), 6.48 (d, 1H, J=2.3 Hz), 5.29 (s, 2H), 2.95 (s, 6H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[F:14][C:15]1[CH:16]=[C:17](Br)[CH:18]=[C:19]([F:22])[C:20]=1[F:21].C(N(CC)CC)C>C(OC)(C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:14][C:15]1[CH:16]=[C:17]([C:13]#[C:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=2)[CH:18]=[C:19]([F:22])[C:20]=1[F:21]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: C#Cc1ccc(OCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCCCOc1ccc(C#Cc2cc(F)c(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.4 mmol of bis(triphenylphosphine)palladium(II) chloride and 0.2 mmol of CuI are added at room temperature to a mixture of 0.02 m of 4-butoxyphenylacetylene, 0.02 m of 3,4,5-trifluorobromobenzene and 50 ml of triethylamine. The reaction mixture is stirred at room temperature for 2 hours, diluted with methyl tert.-butyl ether and filtered with suction, and the solution is evaporated. Purification by chromatography and/or crystallization gives 3,4,5-trifluoro-4'-butoxytolan.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:16][CH2:17][O:18][C:19](OCC)(OCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=2)[C:9](=[C:19]([O:18][CH2:17][CH3:16])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]1=[O:15])(=[O:34])[CH3:33]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: CCCC(=O)c1ccc2c(c1)CC(=O)N2
Product: CCCC(=O)c1ccc2c(c1)C(=C(OCC)c1ccccc1)C(=O)N2C(C)=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
10 g (49 mmol) 5-butyryl-2-indolinone (Ex. I.2) in 200 ml acetic anhydride are stirred for 5 h at 130° C. Then 35 ml triethyl orthobenzoate are added and the mixture is stirred for a further 4 h at 100° C. It is then evaporated down and the resulting precipitate is suction filtered, washed and dried.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([I:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.O1CCOCC1.Cl.[CH2:22]([O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[ClH:2].[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34][C:3]2[C:12]3[C:7](=[CH:8][C:9]([F:14])=[C:10]([I:13])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:35][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cc2ncnc(Cl)c2cc1I
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1I
Temperature: 110 °C
Yield: 79.1 %

Procedure:
Prepared according to Procedure A from 4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65 mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml) and 4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The mixture was stirred and heated to 110° C. (oil bath temperature) for 16 hours. The mixture was cooled to room temperature and filtered to remove the precipitated solids. The solids were washed with cold anhydrous dioxane (100 ml) followed by cold anhydrous diethyl ether. The yellowish solid was collected and dried under vacuum at room temperature to yield 4.68 grams (79%) of the title compound. δH (400 MHz, DMSO-d6): 11.2 (s, 1H), 9.3 (d, 1H), 8.79 (s, 1H), 7.64 (d, 1H), 7.58 (d, 2H), 7.44 (d, 2H), 7.38 (m, 2H), 7.31 (m, 1H), 7.09 (d, 2H), 5.14 (s, 2H) ESI-MS m/z 472 (M+1).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH2:30][C:31]1[N:36]=[C:35](Cl)[CH:34]=[C:33]([CH3:38])[N:32]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(O)CO>[NH2:30][C:31]1[N:36]=[C:35]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:34]=[C:33]([CH3:38])[N:32]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)nc(N)n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 4.00 g (0.010 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, 1.43 g (0.010 mol) of 2-amino-4-chloro-6-methylpyrimidine, 1.39 ml (0.01 mol) of triethylamine, and 125 ml of ethylene glycol is stirred at 100° C. for 5 hours. The reaction mixture is shaken with aqueous sodium carbonate and methylene chloride and the remaining solid is then collected by filtration. The product, 1-(2-amino-6-methyl-4-pyrimidinyl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (4.06 g, 80%), is crystallized twice from methanol/methylene chloride; it has a melting point of 283°-286° C.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CC(=O)CC>[OH:10][CH2:9][C:2]1[O:3][CH:4]=[C:5]([O:8][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:6](=[O:7])[CH:1]=1
Reactant: ClCCN1CCCC1
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1cc(CO)occ1OCCN1CCCC1

Procedure:
A mixture of kojic acid (28.4 g, 0.20 mole), 300 mL of 2-butanone, potassium carbonate powder (27.6 g, 0.20 mole), potassium iodide (1.66 g, 0.01 mole), and 1-(2-chloro-ethyl)-pyrrolidine (26.7 g, 0.20 mole) is stirred at a gentle reflux overnight. The reaction mixture is cooled, filtered, washed with acetone and the filtrate evaporated. Water is added and extracted with chloroform (3×100 mL) and ethyl acetate (6×100 mL). The combined organics were dried with sodium sulfate and passed through a pad of magnesol and silica gel eluting with ethyl acetate. The eluate is evaporated in vacuo and crystallized with hexane/ethyl acetate (2/1) to give an off-white solid, 3.05 g, (6%); MS (ES+): m/z 240.3 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[C:10]([CH3:40])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:13][CH2:12]2.N1C=CC=CC=1.C1C=CC=CC=1>O>[C:1]([O:8][C:9]1[C:10]([CH3:40])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:13][CH2:12]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of acetic anhydride was added to a mixture of 3.5 g of 6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman (prepared as described in Preparation 15), 10 ml of pyridine and 10 ml of benzene, and the mixture was stirred for 2hours at room temperature. The reaction mixture was then poured into water and extracted with benzene. The extract was washed with 5% w/v aqueous hydrochloric acid and water, successively in that order, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH2:45])[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:45][C:33]1[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][CH2:43][CH2:44]2)=[C:31]([O:30][CH3:29])[CH:32]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2cc(Cl)ccc2[N+](=O)[O-])ccc1OCCN1CCCC1
Reaction time: 1 h

Procedure:
5-Chloro-2-nitrobenzoic acid [Aldrich] (600 mg, 3 mmol) was suspended in dichloromethane (5 ml) and treated with oxalyl chloride (2 ml) and DMF (1 drop). On stirring, an immediate effervescence occurred which ceased after 1 hour. The solvent was removed in vacuo and the residue dissolved in dichloromethane (10 ml) and treated successively with DIEA resin (3.1 mmol/g, 1.95 g) and 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (650 mg, 3 mmol). The mixture was stirred at RT for 16 hours then filtered, evaporated, and the residue purified by flash chromatography (methanol-dichloromethane-aqueous ammonia) to afford 5-chloro-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-nitro-benzamide as a yellow foam;
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[C:36]([CH3:37])=[C:35](B(O)O)[C:34]([CH3:41])=[N:33]1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:35]2[C:34]([CH3:41])=[N:33][N:32]([CH3:31])[C:36]=2[CH3:37])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(C)c(C)c1B(O)O
Reactant: CCCS(=O)(=O)c1cccc(C#Cc2cc(Br)ccc2OCC(=O)OC(C)(C)C)c1
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(-c3c(C)nn(C)c3C)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 192, starting from tert-butyl(4-bromo-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate (Intermediate 191) and 1,3,5-trimethyl-1H-pyrazole-4-boronic acid, pinacol ester, the title compound was obtained as a black sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:16]1[CH2:19][C:18](=O)[CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([N:4]([CH:18]2[CH2:19][O:16][CH2:17]2)[CH:5]2[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: O=C1COC1
Reactant: CCOC(=O)C1CCC(NC2CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCC(N(C2CC2)C2COC2)CC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 329A (1.05 g) in dichloromethane (10 mL) was added oxetan-3-one (0.358 g) followed by sodium triacetoxyborohydride (1.05 g). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with 2N aqueous NaOH, water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][C:4]#[CH:5].[NH2:7][C:8]([CH3:19])([CH3:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[CH3:19][C:8]([NH:7][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])([CH3:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: C#CCCC=O
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C#CCCCNC(C)(C)CNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 4-pentynal (631 mg) synthesized according to the method described in U.S. Pat. No. 4,877,779 A1 and tert-butyl (2-amino-2-methylpropyl)carbamate (328 mg) in methylene chloride (10 mL), sodium triacetoxyborohydride (921 mg) and acetic acid (99 μL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 80% ethyl acetate in methanol) to obtain tert-butyl (2-methyl-2-((4-pentyn-1-yl)amino)propyl)carbamate (G7, 172 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4].[Cl:13]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([Cl:13])=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccn(C(F)F)n1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nn(C(F)F)cc1Cl
Temperature: 50 °C

Procedure:
A mixture of 1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (535 mg, 3 mmol) and N-chloro-succinimide (1.22 g, 9.1 mmol) in N,N-dimethylformamide (5 ml) was heated at 50° C. overnight. The reaction mixture was cooled, poured into water (20 ml), then extracted with ethyl acetate. The organic layer was separated, washed with water, dried over sodium sulphate, finally evaporated at reduced pressure. The yellowish crude material was purified by chromatography on silica gel using a 3:1-mixture of cyclohexane and ethyl acetate as the eluent. The 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester was obtained as a white solid (540 mg, 84% of theory). MS (ISP): m/z=209.9 [M]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(OCCO)C>[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCCO
Product: N#Cc1cnc2ccsc2c1NCc1ccc(Cl)cc1Cl
Yield: 75.9 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol), 2,4-dichlorobenzylamine (217.6 mg, 0.17 mL, 1.24 mmol), N,N-diisopropylethylamine in 5 mL of 2-ethoxyethanol is heated at reflux for 4 hours. After cooling the mixture is concentrated in vacuo and the residue is treated with a saturated aqueous sodium bicarbonate solution for 1 hour. The precipitate is collected by filtration, washed with water, dried in vacuo, and then purified by flash column chromatography eluting with a gradient of 2% methanol in dichloromethane to 4% methanol in dichloromethane to provide 261.2 mg of 7-[(2,4-dichlorobenzyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 215–216° C.; 1H NMR (DMSO-d6) δ 4.95 (d, J=5 Hz, 2H), 7.28 (d, J=6 Hz, 1H), 7.40 (dd, J=6, 2 Hz, 1H), 7.46 (dd, J=4, 2 Hz, 1H), 7.69 (d, J=2 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.16 (m, 1H) 8.47 (d, J=6 Hz, 1H); MS 334.0, 335.8 (M+H)+.