Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)=[CH:8][C:7]([CH3:22])=[CH:6][CH:5]=2.[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=1.C(OC(=O)C)(=O)C>>[CH3:32][N:31]([CH3:33])[C:27]1[CH:26]=[C:25]([N:24]([CH3:34])[CH3:23])[CH:30]=[CH:29][C:28]=1[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=3)[NH:3][C:2]=2[CH3:1])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:17]1
Reactant: Cc1ccc2[nH]c(C)c(C(=O)c3ccccc3C(=O)O)c2c1
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2[nH]c(C)c(C3(c4ccc(N(C)C)cc4N(C)C)OC(=O)c4ccccc43)c2c1
Yield: 76.4 %

Procedure:
A mixture of 2.0 g (0.007 mole) of 2-[(2,5-dimethyl-3-indolyl)carbonyl]benzoic acid from part A above, 1.1 g (0.007 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and seven ml of acetic anhydride was interacted in a manner similar to that described in Example 3, part E above, to obtain 2.35 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(2,5-dimethyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =R6 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; Y1 =CH3), a light purple solid melting over the range of 100°-125° C. The infrared showed a characteristic absorption maximum at 1760 cm-1 (C=O; s). A toluene solution of this product spotted on acid clay or phenolic resin developed an intense violet-colored image.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][C:15]3([CH3:31])[CH2:24][C:23](=O)[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=4)[O:16]3)=[CH:11][CH:10]=2)[S:3]1.[BH4-].[Na+]>C(O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][C:15]3([CH3:31])[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]=4)[O:16]3)=[CH:11][CH:10]=2)[S:3]1
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)C=CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 2.7 g of ethyl 2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2-methyl-4-oxochroman-6-carboxylate (prepared as described in Example 14), 0.33 g of sodium borohydride and 40 ml of ethanol were used, to prepare the 4-hydroxy compound corresponding to the title compound. Using a procedure similar to that described in Preparation 3, this hydroxy compound was treated, without purification, with 0.1 g of p-toluenesulfonic acid monohydrate, 30 ml of benzene and 5 ml of dioxane, to afford 2.25 g of the title compound as a pale yellow glassy substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][NH:11][NH2:12]>C(O)C>[Br:1][C:2]1[C:3]([CH:8]=[N:12][NH:11][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ncccc1Br
Reactant: CNN
Solvent: CCO
Product: CNN=Cc1ncccc1Br
Temperature: 80 °C
Yield: 99.1 %

Procedure:
3-bromo-2-formylpyridine (5 g, 26.88 mmol) and methylhydrazine (1.70 mL, 32.25 mmol) are dissolved in ethanol (10 mL) and heated at 80° C. for 2 h. Volatiles are removed under reduced pressure and the residue is re-evaporated several times to give N-[1-(3-Bromo-pyridin-2-yl)-methylidene]-N′-methyl-hydrazine (5.70 g, 99%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:13][C:12]1=[O:18]
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (57 mg, 66%).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+].O.[C:14]1(S(OCC#C)(=O)=O)[CH:19]=CC=C[CH:15]=1>C1(C)C=CC=CC=1>[CH2:19]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[C:14]#[CH:15]
Reactant: C#CCOS(=O)(=O)c1ccccc1
Reactant: NC1CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCNC1CCc2ccccc21
Yield: 62 %

Procedure:
To a mixture of racemic 1-aminoindan (64 g), 15% aqueous sodium hydroxide solution (141 g), water (107 mL) and toluene (192 mL) there was added propargyl benzenesulfonate (94.3 g) during 20 minutes at ambient temperature. The resulting mixture was heater to 45° C. for 4 hours, at which time the pH was confirmed to be >12(45% sodium hydroxide added if necessary) and the phases were separated. To the organic phase water (64 mL) was added and the pH was adjusted to 2 with 33% aqueous sulfuric acid. The aqueous phase was separated, diluted with water and mixed with toluene. The pH was adjusted to 6 with 25% aqueous sodium hydroxide and the phases separated. The aqueous phase was extracted again with toluene, ensuring a pH=6. The combined organic layers were concentrated in vacuo to yield 51 g of crude racemic N-propargyl-1-aminoindan as a yellow oil.
Reaction SMILES: [C:1]12([CH2:11][C:12]([NH:14][C:15]3[C:16]4[CH2:24][CH2:23][NH:22][CH2:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:26][CH2:27][CH2:28][OH:29].CCN(C(C)C)C(C)C>CCO>[C:1]12([CH2:11][C:12]([NH:14][C:15]3[C:16]4[CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[O:13])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: OCCCBr
Reactant: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ncnc2c1CCNC2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ncnc2c1CCN(CCCO)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
A solution of 2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-acetamide (0.05 g, 0.153 mmol), 3-bromo-1-propanol (0.021 g, 0.15 mmol) and DIPEA (0.045 g, 0.35 mmol) in EtOH (4 mL) was stirred at 75° C. for 17 h. The reaction vessel was allowed to cool to room temperature, opened, and the volatiles were removed on a rotary evaporator. The residue was redissolved in THF (3 mL). PL-NCO resin (300 mg) was added, and the resulting suspension was stirred at room temperature for 16 h. The resin was filtered and the volatiles were removed under vacuum. The crude product was purified by HPLC to afford 2-adamantan-1-yl-N-[7-(3-hydroxy-propyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-acetamide (0.0098 g, 17%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([O:25]C)=[O:24])=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([OH:25])=[O:24])=[O:15])=[CH:12][CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C(=O)OC)cc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C(=O)O)cc1)OCC

Procedure:
To a solution of 0.73 g of 4-diethoxyphosphinylmethyl-N-(2-methoxycarbonylphenyl)benzamide in 10 ml of ethanol was slowly added 10 ml of 1N sodium hydroxide under ice-cooling with stirring. After stirring for 5 hours at room temperature, 10 ml of 2N hydrochloric acid was added thereto, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The crystalline residue was recrystallized from benzene to give 0.60 g of colorless plate crystal of 4-diethoxyphosphinylmethyl-N-(2-carboxyphenyl)benzamide. mp: 171°-172° C.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C@@H:11]([O:13][CH2:14][C@H:15]([O:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][N:37]=3)[N:34]=[CH:35][C:28]=12)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=1)=[O:17])[CH3:12])(C(C)(C)C)(C)C>C1COCC1.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16](=[O:17])[C@@H:15]([O:26][C:27]2[N:32]=[CH:31][N:30]=[C:29]3[N:33]([C:36]4[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][N:37]=4)[N:34]=[CH:35][C:28]=23)[CH2:14][O:13][C@@H:11]([CH3:12])[CH2:10][OH:9])=[N:20][CH:21]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
HCl (4M in Dioxane) (0.606 mL, 2.42 mmol) was added to (2S)-3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-N-(5-chloropyridin-2-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AO4) (300 mg, 0.48 mmol) in THF (5 mL) and water (0.5 mL) at room temperature. The resulting solution was stirred at room temperature for 10 minutes. The reaction mixture was evaporated and the residue partitioned between EtOAc (25 mL) and sat NaHCO3 (10 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by preparative chiral-HPLC on a Merck 50 mm 20 μm Chiralpak AS column, eluting isocratically with 30% EtOH in isohexane (modified with Et3N) as eluent. The fractions containing the desired compound were evaporated to dryness to afford the product (173 mg, 70.7%). 1H NMR (400 MHz, CDCl3) δ 1.17 (d, 3H), 2.64 (s, 1H), 3.51-3.67 (m, 2H), 3.69-3.79 (m, 1H), 4.11-4.28 (m, 2H), 6.05 (t, 1H), 7.45-7.50 (m, 1H), 7.66-7.71 (m, 1H), 7.99-8.04 (m, 1H), 8.18-8.25 (m, 2H), 8.47 (s, 1H), 8.60-8.65 (m, 2H), 9.10 (s, 1H) m/z (ESI+) (M+H)+=504.40; HPLC tR=1.96 min
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([NH2:6])(=[O:5])=[O:4].[F:9][C:10](=[C:15]([F:17])[F:16])[CH2:11][C:12](Cl)=[O:13]>[OH-].[Na+]>[F:9][C:10](=[C:15]([F:17])[F:16])[CH2:11][C:12]([NH:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])=[O:13]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=C(Cl)CC(F)=C(F)F
Agent: [Na+]
Agent: [OH-]
Product: O=C(CC(F)=C(F)F)NS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 16.4 %

Procedure:
To an ice-cold solution of trifluoromethanesulfonamide (2.75 g, 18.4 mmol) in 7.4 mL of 2.5N sodium hydroxide was added 3,4,4-trifluoro-3-butenoyl chloride (2.93 g, 18.5 mmol) with stirring in 2 min. The mixture was stirred in cold for 30 min and the white precipitate formed was filtered, washed with cold water (10 mL) and dried to give 0.82 g (16%) of the desired product as a white solid. m.p. 115°-120° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.O>CN(C)C=O>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: ClCc1cccs1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1csc(Cn2cnc3ccccc32)c1
Reaction time: 0.5 h

Procedure:
To 11.81 g of benzimidazole in 50 ml of dimethylformamide was added 4.8 g of 50% sodium hydride in oil over 30 minutes. After stirring 30 minutes, 13.25 g of 2-chloromethylthiophene was added over a period of 30 minutes, and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the pH adjusted to 1.5. After extracting with ether, the pH was raised to 11 and precipitated product was filtered and dried, 19.9 g.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6][N:5]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:4](=[O:16])[C:3]=1[C:17]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([N+:27]([O-])=O)=[CH:26][C:20]=2[S:19](=[O:31])(=[O:30])[N:18]=1.NN>CO.C1COCC1.[Ni]>[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:3]3[C:4](=[O:16])[N:5]([CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[N:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]=3[OH:1])=[N:18][S:19](=[O:30])(=[O:31])[C:20]=2[CH:26]=1
Reactant: CC(C)CCn1nc(C(C)C)c(O)c(C2=NS(=O)(=O)c3cc([N+](=O)[O-])ccc3N2)c1=O
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCn1nc(C(C)C)c(O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a solution of 5i (0.100 g, 0.22 mmol) in MeOH (5 mL) and THF (5 mL) was added Raney-Nickel (0.6 mL, 50% slurry in H2O) followed by anhydrous NH2NH2 (0.3 mL, 9.56 mmol). The reaction mixture was stirred 15 min at ambient temperature, filtered using a syringe filter with 0.2 μm PTFE membrane, and concentrated in vacuo. The crude mixture was purified by flash column chromatography using silica gel eluted with 0-3% MeOH/CH2Cl2 to give 5j (0.072 g, 77%) as a red solid. 1H NMR (400 MHz, D6-DMSO) δ 7.0 (br s, 1 H), 6.93 (s, 1 H), 6.79 (d, J=2.8 Hz, 1 H), 6.76 (d, J=2.4 Hz), 5.33 (br s, 2 H), 3.86 (t, J=6.8 Hz, 2 H), 3.22 (m, 1 H), 1.52 (m, 3 H), 1.08 (d, J=7.2 Hz, 6 H), 0.90 (d, J=6.4 Hz, 6 H). MS(ESI+) m/e 420 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:50][C:51]1[N:59]=[CH:58][CH:57]=[C:56]([CH3:60])[C:52]=1[C:53](O)=[O:54].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:50][C:51]1[N:59]=[CH:58][CH:57]=[C:56]([CH3:60])[C:52]=1[C:53]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:10][CH2:11]1)[CH3:5])=[O:54]
Reactant: Cc1ccnc(Cl)c1C(=O)O
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (0.077 g, 0.20 mmol), EDCI (0.043 g, 0.22 mmol) and HOBT (0.030 g, 0.22 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-chloro-4-methyl-nicotinic acid (0.038 g, 0.22 mmol) followed by DIPEA (42 μL, 0.24 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 90:8:2, v/v/v) afforded 2-chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide (0.062 g, 57%) as a white foam. 1H NMR (CDCl3) δ 0.98 (d, 3H, J=6.0 Hz), 1.06 (m, 1H), 1.22 (m, 1H), 1.57 (m, 2H), 1.81 (m, 3H), 2.11 (br t, 1H), 2.36 (s, 6H), 2.53 (br t, 1H), 2.75-2.88 (m, 3H), 3.20-3.33 (m, 2H), 3.71 (s, 3H), 3.82 (m, 1H), 3.90 (m, 2H), 6.63 (d, 2H, J=9.0 Hz), 6.71 (d, 2H, J=9.0 Hz), 6.96 (d, 1H, J=6.0 Hz), 7.03 (d, 1H, J=6.0 Hz), 7.98 (d, 1H, J=6.0 Hz), 8.25 (s, 1H), 8.30 (d, 1H, J=3.0 Hz), 8.42 (br s, 1H). 13C NMR (CDCl3) δ 13.3, 18.9, 19.1, 29.6, 30.4, 30.9, 39.9, 43.8, 47.0, 51.9, 55.5, 59.2, 60.0, 114.4, 119.9, 124.2, 125.1, 148.0, 149.0, 149.3. ES-MS m/z 536 (M+H), 558 (M+Na). Anal. Calcd. for C30H38N5O2Cl.0.2 CH2Cl2: C, 65.58; H, 7.00; N, 12.66. Found: C, 65.64; H, 7.15; N, 12.79.
Reaction SMILES: [CH2:1]([CH2:6][CH2:7][NH2:8])[CH2:2][CH2:3][CH2:4][NH2:5].[C:9]([O:16][CH2:17][CH3:18])(=[O:15])[C:10]([O:12]CC)=O>C(O)C>[CH2:17]([O:16][C:9](=[O:15])[C:10]([NH:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:6][CH2:7][NH:8][C:10](=[O:12])[C:9]([OH:16])=[O:15])=[O:12])[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: NCCCCCCN
Solvent: CCO
Product: CCOC(=O)C(=O)NCCCCCCNC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
The method of Example II in U.S. Pat. No. 2,343,808 was used. Molten HMDA (27.1 grams) was poured into a solution of diethyl oxalate (136 grams) in ethanol (127 mL) and stirred for 18 hours. The solid was collected by filtration, dissolved in CH2Cl2 (150 mL) and purified by flash column chromatography (EtOAc as the eluent). The resulting solid was boiled in MTBE (150 mL), cooled to ambient temperature, and then collected by filtration to obtain 19.8 grams of hexamethylene-bis-oxamic acid ethyl ester as white needles having a melting point in the range of 91.6 to 92.5° C. 1H NMR (CDCl3, 300 MHz) δ 7.13 (brs, 2H), 4.34 (q, J=7.2 Hz, 4H), 3.33 (q, J=6.9 Hz, 4H), 1.59-1.52 (m, 4H), 1.37 (t, J=7.2 Hz, 6H), 1.39-1.34 (m, 4H).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH2:11]([O:13][C:14](=[O:29])[CH:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:12]>CC(C)=O>[CH2:11]([O:13][C:14](=[O:29])[CH:15]([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:12]
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Reaction time: 60 h

Procedure:
153 g (1.1 mol) of p-nitrophenol, 1.3 liters acetone and 336 g (1.0 mol) of ethyl-α-bromo-tetradecanoate were placed in a 5-liter 3-necked flask and heated on a steam bath with stirring, for 60 hours. The product was filtered to remove inorganic salt and then the acetone was distilled off under vacuo. The residual oil was taken up in hexane, filtered, and concentrated under vacuo. Yield of Intermediate I was 361 g. TLC Analysis (benzene) showed only one spot, indicating a single product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9](Br)[CH:8]=[N:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>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.[Cu]I.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cncc(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of ethyl-5-bromonicotinate (30 g, 130.40 mmol), triethylamine (78 mL) and ethyl acetate (130 mL) is degassed for 15 min. Add trimethylsilylacetylene (88.46 mL, 625.92 mmol), bis(triphenylphosphine)palladium (II) dichloride (4.57 g, 6.52 mmol) and copper (I) iodide (0.25 g, 1.30 mmol) and stir at 50° C. under-nitrogen for 16 h. Cool to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with 10:1 hexanes:ethyl acetate, to give the title compound (27.7 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:18](N)=[NH:19]>C(O)C>[N+:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:6])=[N:19][CH:18]=[N:1]2)=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: N=CN
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(O)ncnc2c1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a solution of 2-amino-4-nitrobenzoic acid (6.00 g, 32.94 mmol) in ethanol (40 mL) was added formamidin acetate (6.80 g, 65.32 mmol). The reaction mixture was refluxed for 5 h and cooled to room temperature and refrigerated. The precipitate was filtered out, washed with several portions of cooled ethanol, and then dried in vacuo to give 5.60 g (89%) of 7-nitroquinazolin-4-ol as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:22])([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)[CH2:3][NH:4][CH2:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7].C=O.[C:25](O)(=O)C>C1COCC1>[F:1][C:2]([F:22])([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)[CH2:3][N:4]([CH3:25])[CH2:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7]
Reactant: CCCCOc1cccc(C(F)(F)CNCC(=O)N(C)C)c1
Reactant: CC(=O)O
Agent: C=O
Solvent: C1CCOC1
Product: CCCCOc1cccc(C(F)(F)CN(C)CC(=O)N(C)C)c1
Reaction time: 1 h
Yield: 65 %

Procedure:
107.5 mg (0.34 mmol) of the free base of 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide (see Example 1-1) are dissolved in dry THF (10 mL). To this solution, formaldehyde (36.5% water solution, 52.1 μL; 0.69 mmol), acetic acid (2.5 mL), and MP-CNBH3 (2.3 mmol/g; 325 mg; 0.75 mmol) are added sequentially. After stirring 1 hour the reaction is completed. After further stirring for 1.5 hours, the reaction mixture is evaporated. The crude residue is flash-chromatographed on silica gel using DCM/MeOH (99.5/0.5) as an eluant. 73.1 mg (65%) of pale yellow fluid 2-{[2,2-difluoro-2-(3-butoxyphenyl)-ethyl]-methylamino}-N,N-dimethyl-acetamide are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH:28]12[O:37][CH:32]([O:33][CH:34]1[CH2:35][OH:36])[CH2:31][NH:30][CH2:29]2>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:30]2[CH2:31][CH:32]3[O:37][CH:28]([CH:34]([CH2:35][OH:36])[O:33]3)[CH2:29]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: OCC1OC2CNCC1O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CC4OC(CO)C(C3)O4)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (400 mg; 0.96 mmol; 1 eq), is dissolved in anhydrous DCM (40 ml). The reaction is put under nitrogen. Triethylamine (0.67 ml; 4.81 mmol; 3 eq) and (6,8-Dioxa-3-aza-bicyclo[3.2.1]oct-7-yl)-methanol (349.2 mg; 2.41 mmol; 2.5 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (450 mg; 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH2:8][C:7]2([CH3:15])[CH3:14])([O-])=O.[OH-].[Na+]>Cl>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH2:8][C:7]2([CH3:15])[CH3:14]
Reactant: CN1CC(C)(C)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1CC(C)(C)c2cc(N)ccc21
Yield: 80 %

Procedure:
5-Nitro-1,3,3-trimethyl-indoline (8.16 g, 40 mmole) was added to a solution of stannous chloride (53 g, 280 mmole) in 200 ml hydrochloric acid with stirring. The mixture was gently refluxed for 16 hrs. The cold reaction mixture was poured onto crushed ice, made alkaline with a concentrated solution of sodium hydroxide and extracted with ethyl acetate (4×200 ml). The combined ethyl acetate solutions were dried with anhydrous sodium sulphate and decolorized with a small amount of active carbon. Solvent was removed and the residue re-crystallized from ethyl acetate to 5.96 g of a yellow solid, an 80% yield of 5-amino-1,3,3-trimethyl-indoline.