Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>ClCCl>[Si:20]([O:10][CH2:9][CH2:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCNc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCNc1ccccc1
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To a stirred solution of 2-(phenylamino)ethanol (10 g, 72.9 mmol, Eq: 1.00) in dichloromethane (200 ml) were added diisopropylethylamine (13.2 g, 17.8 ml, 102 mmol, Eq: 1.4) followed by tert-butyldimethylsilyl chloride (11.0 g, 72.9 mmol, Eq: 1.00) at room temperature under a nitrogen atmosphere. The resulting solution was stirred for 16 hrs and then it was poured into water (200 ml) and the organic layer was separated, washed with brine, dried (MgSO4), concentrated, and chromatographed (silica gel, gradient 0 to 10% ethyl acetate-hexane) to obtain N-(2-(tert-butyldimethylsilyloxy)ethyl)aniline (46) (8.45 g, 33.6 mmol, 46.1% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:34]([C:36]([CH3:39])([CH3:38])[CH3:37])#[C-:35]>CO.O>[C:36]([NH:34][C:35]1[N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=[CH:5][C:6]2=[N:9][C:16]=1[C:15]1[CH:14]=[C:13]([Cl:12])[CH:20]=[C:19]([Cl:21])[CH:18]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)Nc1c(-c2cc(Cl)cc(Cl)c2)nc2ccc(C(F)(F)F)cn12
Temperature: 25 °C
Yield: 46.7 %

Procedure:
5-(trifluoromethyl)pyridin-2-amine (200 mg, 1.23 mmol, Eq: 1.00), 3,5-dichlorobenzaldehyde (227 mg, 1.3 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (70.4 mg, 370 μmol, Eq: 0.3) were dissolved in MeOH (1.5 mL). The resulting colorless solution was stirred at rt. To this solution was added dropwise 2-isocyano-2-methylpropane (103 mg, 140 μL, 1.23 mmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2 h. To the yellow clear solution was added dropwise water until the mixture got turbid. After stirring for a few additional minutes, the product precipitated. The solid was filtered off, washed with MeOH/water (1:1) and with hexane and the crystals were dried under vacuum to yield a white solid (231 mg, 46.5%). MS: 402 [M]+; 1H-NMR (D6-DMSO): δ 8.91 (s, 1H), 8.30 (d, 2H), 7.73 (d, 1H), 7.57 (t, 1H), 7.49 (d, 1H), 5.05 (s, 1H), 1.07 (s, 9H).
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[C:9]([CH:22]=1)[C:10]([O:12]CC1C=CC(F)=C(F)C=1)=[O:11].Cl>O1CCCC1.C(OCC)(=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[C:9]([CH:22]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(OCc1ccc(F)c(F)c1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(F)c(F)c1

Procedure:
Water (50 ml) and lithium hydroxide (0.60 g, 24.93 mmol) were added to a solution of (3,4-difluorophenyl)methyl 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}benzoate (may be prepared by Description 88; 3.9 g, 8.31 mmol) in tetrahydrofuran (150 ml). The mixture was heated to reflux for 2 hours. The mixture was allowed to cool and diluted with ethyl acetate (200 ml) and this mixture was then acidified to pH=1 using 2M aqueous HCl. The organics were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The organics were combined, dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a white solid. 2.9 g. The residue contains some benzyl alcohol.
Reaction SMILES: [F:1][C:2]([F:19])([C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][C:5](OC)=O.[F:20][C:21]([F:36])([C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:22][CH2:23][CH2:24][NH2:25].C[OH:38]>>[F:1][C:2]([F:19])([C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[CH2:3][CH2:4][CH2:5][CH:23]([CH2:22][C:21]([F:36])([F:20])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])[C:24]([NH2:25])=[O:38]
Reactant: CO
Reactant: COC(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: NC(=O)C(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 80 %

Procedure:
A mixture of methyl 4,4,5,5,6,6,7,7,7-nonafluoroheptanoate (18 g 59 mmol) and 4,4,5,5,6,6,7,7,7-nonafluoroheptylamine (18.5 g, 66.8 mmol) was heated to slowly distill MeOH out through a 15 cm long column. Colorless liquid (10.5 g) was obtained by atmospheric and then full vacuum distillation. After being cooled to RT, the residue in the reaction flask was solidified to a yellow solid (26.0 g). NMR and GC-MS analysis indicated that it was the product, N-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-4,4,5,5,6,6,7,7,7-nonafluoroheptanamide, 80% yield. 19F NMR (CDCl3) -81.6 (t, J=10Hz, 6F), -115.0 (m, 2F), -115.4 (m, 2F), -125.0 (m, 4F), -126.6 (m, 4F) ppm. 1H NMR (CDCl3) 1.85 (m, 2H), 2.12 (m, 2H), 2.42-2.61 (m, 4H), 3.38 (q, J=7 Hz, 2H), 5.70 (br s, 1H) ppm. 13C NMR (CDCl3) 21.0 (s), 26.9 (t, J=23 Hz), 27.3 (s), 28.5 (t, J=23 Hz), 39.0 (s), 170.0 (s), 115-122 (m) ppm. MS (m/e) 532 (M+ -F, 37.5%), 482 (M+ -CF3, 0.3%), 382 (M+ -C3F7, 20.5%), 332 (M+ -C3F7, 58.7%), 275 (88.1%), 169 (1.8%), 119 (26.7%), 69 (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:20]([C:17]1[NH:18][N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])[CH3:25]
Reactant: CCN
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Product: CCNC(=O)c1cc(NCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Yield: 41 %

Procedure:
As described for example 152, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid was converted, using ethylamine instead of 2-hydroxy-2-methypropylamine, to the title compound (14 mg, 41%) which was obtained as an off white solid. MS: m/e=344.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:3]=1.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN1CCCC1=O.C(OCC)(=O)C.O>[C:28]([O:27][C:26](=[O:32])[NH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:3]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: Cn1ccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cn1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 150 °C
Yield: 17.6 %

Procedure:
6-Chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid amide (60 mg, 0.237 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (102 mg, 0.475 mmol) were dissolved in N-methylpyrrolidinone (1.5 mL). The reaction mixture was heated at 150° C. for 16 h, then additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (100 mg, 0.47 mmol total) was added in three portions over 6 d. The reaction mixture was cooled, diluted with ethyl acetate and water, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, and then dried (sodium sulfate), filtered, and concentrated in vacuo. The residue obtained was purified by chromatography (silica, 0 to 7% methanol in dichloromethane) to give {(1S,2R)-2-[6-carbamoyl-5-(1-methyl-1H-pyrazol-3-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (18 mg, 17%) as a brown amorphous residue. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.68-10.80 (m, 1H) 7.89-8.06 (m, 1H) 7.34-7.37 (m, 1H) 7.25 (d, J=2.3 Hz, 1H) 5.93 (d, J=2.3 Hz, 1H) 5.56-5.64 (m, 1H) 5.02-5.14 (m, 1H) 3.91-4.01 (m, 1H) 3.86 (s, 3H) 1.55 (br. s., 8H) 1.40 (s, 9H); LCMS (EI/CI) m/z: 431 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]3C[O:27]3)[C:20]=2C=O)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C([C:38](OO)=[O:39])C=1.CC(C)=O.ClCCl>ClCCl>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][CH2:25][C@@H:26]([CH2:38][OH:39])[O:27][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc(OC[C@@H]3CO3)c(C=O)c21)NC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: ClCCl
Product: C[C@@H](Cn1ncc2ccc3c(c21)O[C@H](CO)CO3)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a stirred solution of the epoxide from Step A (0.86 g, 2.10 mmol) in dichloromethane (100 mL) was added m-chloroperbenzoic acid (70%, 0.62 g, 2.52 mmol) in portions under nitrogen atmosphere. After the addition completed the reaction mixture was stirred overnight. The reaction was quenched by a saturated aqueous solution of sodium thiosulfate (20 mL) and dichloromethane was evaporated. To the aqueous residue was added potassium carbonate (1.0 g) and methanol (200 mL), the resulting mixture was stirred for ½ h and organic solvent was evaporated. The residue was extracted with ethyl acetate (50 mL×3), dried and evaporated to dryness to afford an oil. Chromatography on silica eluting with a gradient of 0% to 10% acetone/dichloromethane gave an oil (0.50 g, 60%). LCMS (+APCI) m/z 397 (M+H), 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.33-7.13 (m, 5H), 7.14 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 5.04-4.97 (m, 3H), 4.65 (ddd, J=6.6, 13.4, 51.6 Hz, 2H), 4.32 (m, 3H), 4.08 (m, 2H), 3.91 (m, 2H), 1.18(d, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([OH:17])=[O:16])=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl:27]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([Cl:27])(=[O:17])=[O:16])=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(S(=O)O)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)Cl)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 51.9 %

Procedure:
N-(3,4-Dichlorobenzyl)-2-ethoxycarbonylindole-3-sulphinic acid (0.48 g), N-chlorosuccinimide (0.16 g) and triethylamine (0.16 ml) were stirred in dichloromethane for 4 hours. The reaction was then concentrated in vacuo and the residue purified by chromatography using iso-hexane:10% ethyl acetate as eluent to give the product as a white crystalline solid (0.27 g, 52%); NMR d (CD3SOCD3) 1.43 (t, 3H), 4.48 (q, 2H), 5.53 (s, 2H), 6.98 (m, 1H), 7.30-7.50 (m, 5H), 8.22 (m, 1H); M/z (−) 444 (M−H+), 426, 410.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([NH2:5])[CH3:4].[CH3:6][C:7]([CH:9]=O)=O.C(C=O)=O>>[CH3:1][N:2]1[CH:6]=[C:7]([CH3:9])[N:5]=[C:3]1[CH3:4].[CH3:1][N:2]1[CH:9]=[C:7]([CH3:6])[N:5]=[CH:3]1
Reactant: CCN
Reactant: CC(=O)C=O
Reactant: CN
Agent: O=CC=O
Product: Cc1cn(C)c(C)n1
Product: Cc1cn(C)cn1

Procedure:
The same procedure as in Example 1 was performed except that 38 parts of methylamine (as a 40% aqueous solution) was used in lieu of ethylamine (as a 70% aqueous solution), and 87 parts of methyl glyoxal was used in lieu of glyoxal (as a 40% aqueous solution). After the dropwise addition, a mixture comprising 1,2,4-trimethylimidazole (a-3) and 1,4-dimethylimidazole (b-3) was obtained. The obtained mixture was analyzed with HPLC to find that the weight ratio of (a-3) to (b-3) was 80:20. The mixture was further purified by distillation under the temperature and pressure conditions of 110° C. and 1.0 kPA, and the weight ratio of (a-3) to (b-3) after the purification was 85:15 (M-11). The obtained mixture was treated in the same manner as in Example 1 to obtain a mixture comprising 1,2,3,4-tetramethylimidazolium tetrafluoroborate (hereinafter, referred to as “TeMI”) and 1,3,4-trimethylimidazolium tetrafluoroborate (hereinafter, referred to as “4TMI”). By the HPLC analysis, the weight ratio between them was found to be 85:15. 212 g of the obtained mixture comprising TeMI and 4TMI was dissolved in propylene carbonate homogeneously so as to adjust the total amount to 1 liter to prepare the electrolyte solution of the present invention.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[C:18]([C:26]([OH:28])=[O:27])=[CH:19][N:20]2[CH:23]2[CH2:25][CH2:24]2)=[CH:15][C:14]=1[F:30])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[C:18]([C:26]([OH:28])=[O:27])=[CH:19][N:20]2[CH:23]2[CH2:24][CH2:25]2)=[CH:15][C:14]=1[F:30]
Reactant: CC(C)(C)OC(=O)NCCCNc1cc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCNc1cc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Yield: 135.8 %

Procedure:
A solution of intermediate 12 (100 mg) in 10% TFA/DCM (1 mL) was stirred at room temperature for 2 h. The solvent was partially evaporated under reduced pressure. For five times the residual was diluted in DCM (2 mL) and concentrated under reduced pressure. Final solvent evaporation afforded the title compound (103.4 mg).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH:10]=[O:11])=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.[H-].[Na+].[C:14]1([C:20]([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)[O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH:28](Br)[CH3:29])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>C1COCC1.ClCCl>[C:14]1([C:20]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:9]2[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]([CH:10]=[O:11])=[CH:8]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(Br)OCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cn(CCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc12

Procedure:
To 1.01 g of indole-3-carboxyaldehyde (6.95 mmol) dissolved in 250 mL THF is added 0.28 g of sodium hydride (11 mmol). After heating the reaction to reflux for 3 hours under nitrogen, 5.0 g of 2-(2-triphenylmethoxyethoxy)ethoxy-1-bromo-ethane (11 mmol) is added. The reaction is allowed to reflux for an additional 16 hours, monitoring by TLC (9:1-ethyl acetate:dichloromethane on alumina). Upon complete consumption of the indole-3-carboxyaldehyde, the reaction is quenched via addition of 25 mL MeOH and the solvent is removed via evaporation. The residue is resuspended in 250 mL dichloromethane and washed 3×200 mL saturated NH4CO3, followed by drying over anhydrous Na2SO4. The crude product is purified via column chromatography over alumina, eluting in dichloromethane with an ethyl acetate gradient.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH3:79])[C:63]=1[N:64]1[CH2:70][CH2:69][CH:68]([F:71])[CH:67]([NH:72][C:73](=[O:78])[C:74]([F:77])([F:76])[F:75])[CH2:66][CH2:65]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:12]1[S:13][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[C:10]([C:22](=[O:23])[NH:58][C:59]2[CH:60]=[N:61][N:62]([CH3:79])[C:63]=2[N:64]2[CH2:65][CH2:66][CH:67]([NH:72][C:73](=[O:78])[C:74]([F:75])([F:76])[F:77])[CH:68]([F:71])[CH2:69][CH2:70]2)[N:11]=1
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (784 mg, 2.2 mmol) in DCM (40 mL) was added PyBOP (1.46 g, 2.8 mmol) and the mixture stirred at room temperature for 30 min. A solution of N-(1-(4-Amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide (647 mg, 2.0 mmol) and DIPEA (0.59 mL, 3.4 mmol) in DCM (40 mL) was then added and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with DCM (60 mL) and washed with water (30 mL). The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-fluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (1.32 g).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[OH-].[K+].[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)([O-:15])=[O:14]>O.CO>[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:4]1[CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH:3]=1)([O-:15])=[O:14]
Reactant: O=C1CN2CCC1CC2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CN4CCC3CC4)c2c1
Reaction time: 48 h

Procedure:
44.8 mmol of 1-azabicyclo[2.2.2]octan-3-one hydrochloride (3-quinuclidinone hydrochloride) and 112 mmol of potassium hydroxide are added to a solution of 22.4 mmol of 5-nitro-1H-indole in 100 ml of water/methanol (1/1), and the mixture is stirred at the boiling point for 48 hours. The crystals which deposit on cooling of the reaction solution are filtered off, washed and dried, giving 3-(5-nitro-1H-indol-3-yl)-1-azabicyclo[2.2.2]-oct-2-ene.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([Cl:8])=[O:7].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>>[ClH:8].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)c1nccs1
Product: COc1cc2nc(N3CCN(C(=O)c4nccs4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The title compound was prepared from thiazole-2-carbonyl chloride (0.79 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.54 g.) following previously described procedures. The product had a m.p. of 273°-276° C. with decomposition.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[C:11](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C>[CH3:11][N:7]1[CH2:8][CH:9]([OH:10])[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6]1
Reactant: OC1CNCc2sccc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2sccc2C(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
4,5,6,7-Tetrahydrothieno[2,3-c]pyridin-4-ol (6.21 g) prepared in Reference Example 5 and 8.29 g of sodium carbonate were suspended in 50 mL of DMF, 6.25 g of methyl iodide was added thereto by dropping thereinto and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured over 200 mL of water and subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo to give 5.63 g of the objective compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:12]([OH:14])[CH3:13].[ClH:15]>C1(C)C=CC=CC=1>[ClH:15].[CH2:12]([O:14][C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=[O:11])[CH3:10])[CH:4]=1)=[NH:2])[CH3:13]
Reactant: CCO
Reactant: CC(=O)c1cccc(C#N)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=N)c1cccc(C(C)=O)c1
Temperature: 0 °C

Procedure:
To an ice-water cooled solution of 29 g. (0.2 mole) of m-cyanoacetophenone in 375 ml. of dry toluene, containing 13 ml. (0.2 mole) of absolute ethanol, is bubbled a stream of hydrogen chloride gas for 2 hours. The solution is allowed to stand in a cold room overnight. The precipitate which forms is collected to give 34 g. of product. A small amount is recrystallized from ethanol (petroleum ether is added to initiate precipitation) to afford a sample with a melting point of 130°-132°.
Reaction SMILES: [CH2:1]([N:3]1[CH:10]=[N:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])[CH3:2].[H][H]>[Rh].O>[CH2:1]([N:3]1[CH2:10][NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])[CH3:2]
Reactant: CCn1cnc(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Rh]
Solvent: O
Product: CCN1CNC(=O)NC1=O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a quantity [370 gm., 2.62 mole] of the 1-ethyl-5-azauracil prepared in Part B, above is added 2200 ml. water and 40 gm. of 5 percent rhodium on activated charcoal. This mixture is put in a Parr hydrogenation chamber and hydrogen gas is introduced to a pressure of 50 pounds per square inch (p.s.i.) and the reaction system is heated to 100° C. When uptake of hydrogen ceases, the hydrogen pressure is increased to 200 p.s.i. and held there for 18 hours. The hydrogenated reaction mixture is rinsed out of the reaction chamber with hot water, filtered while hot, and the filter is washed with one liter of water at 80° C. The aqueous solution is set aside at 25° C. for 18 hours, during which interval crystals form. The crystals are collected on a filter and dried at 50° C. under reduced pressure. There is thus obtained 70 gm. of 5-ethyl-5,6-dihydro-s-triazine-2,4-(1H, 3H)-dione having a melting range between 220° C. and 224° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:14]([O:22][CH3:23])(=[O:21])[C:15]#[C:16][C:17]([O:19][CH3:20])=[O:18]>>[C:9]([O:8][C:7]([NH:6][C:2]1[CH:3]=[CH:4][C:5]([OH:1])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]=1[C:14]([O:22][CH3:23])=[O:21])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1ccco1
Product: COC(=O)c1c(O)ccc(NC(=O)OC(C)(C)C)c1C(=O)OC

Procedure:
reacting tert-butyl furan-2-ylcarbamate with dimethyl but-2-ynedioate via the Diels-Alder reaction to form dimethyl 3-(tert-butoxycarbonylamino)-6-hydroxyphthalate;