Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:26][N:27](C)[C:28](=O)[O:29][C:30]([CH3:33])(C)C)=[CH:4][N:5]([S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[C:6]=1[C:7]1[C:8]([C:13]([F:16])([F:15])[F:14])=[N:9][CH:10]=[CH:11][CH:12]=1.[C:36]([O:39]CC)(=[O:38])[CH3:37].Cl.C([OH:45])C>>[C:30]([OH:29])(=[O:45])/[CH:33]=[CH:37]/[C:36]([OH:39])=[O:38].[F:1][C:2]1[C:3]([CH2:26][NH:27][CH3:28])=[CH:4][N:5]([S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[C:6]=1[C:7]1[C:8]([C:13]([F:16])([F:15])[F:14])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(C)=O
Reactant: CCO
Reactant: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2C(F)(F)F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2C(F)(F)F)c1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl ({4-fluoro-1-(pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-3-yl}methyl)methylcarbamate (506 mg) in ethanol (5 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give the title compound as a free base (307 mg). To a solution of the obtained free base (229 mg) in ethyl acetate (3 mL) was added a solution of fumaric acid (65.1 mg) in ethanol (3 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 209 mg, 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[C:32]1([CH2:38][CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)CCl.C1C=CC2N([OH:54])N=NC=2C=1.CCN(CC)CC>ClCCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29]([CH3:30])=[O:54])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: On1nnc2ccccc21
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 723.2 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (220 mg, 0.50 mmol) in dichloromethane (5 mL) was added (2-phenylethyl)amine (69.1 μL, 0.55 mmol), EDC (105 mg, 0.55 mmol), HOBt (6.8 mg, 0.05 mmol) and Et3N (281 μL, 2.0 mmol). The reaction mixture was stirred at room temperature for 20 hours. Then was quenched with H2O, extracted with DCM, dried over Na2SO4, filtered, concentrated and applied to flash chromatography to afford the titled compound 202 mg (74%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:13]([OH:19])(=[O:18])[CH2:14]C(O)=O.C([O-])(=O)C.[NH4+:24]>CCO>[NH2:24][CH:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)[CH2:14][C:13]([OH:19])=[O:18]
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A mixture of 5 g of 2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde, 3.17 g of malonic acid and 4.69 g of ammonium acetate in 50 ml of EtOH is refluxed for 5 hours. The reaction mixture is allowed to cool to RT and the precipitate formed is filtered off by suction and washed with EtOH and then with water. 1.965 g of the expected product are obtained after drying under vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][OH:35])=[CH:4][N:3]=1.CO.[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH2:32][CH2:33][CH2:34][OH:35])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(CCCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-hydroxyprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (110 mg, 0.228 mmol), methanol (2 mL) and N, N-dimethylforamide (2 mL) was added sodium borohydride (26.9 mg, 0.684 mmol) under an atmosphere of nitrogen. Mixture stirred for 30 minutes at room temperature after which it was treated with 1M sodium carbonate (5 mL) and extracted with dichloromethane (3×5 mL). The organic layer was separated, dried over magnesium sulfate, and filtered, and the solvent was removed under reduced pressure. The product was purified via flash chromatography to furnish the title compound as a pale yellow powder (21.1 mg, 0.0434 mmol): LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 mm particle size, 33×4.6 mm; 70% 50 mM ammonium Acetate in Water to 95% Acetonitrile over 4.5 min, 0.8 mL/min): MH+=487 RT=3.23 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (1H), 7.99 (1H), 7.70 (2H), 7.60 (1H), 7.55 (1H), 7.32–7.35 (2H), 7.21 (1H), 7.15 (1H), 7.07 (1H), 5.34 (2H), 4.04 (3H), 3.91 (3H), 3.47 (2H), 2.75 (2H), 1.83 (4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[C:15]2[C:21](=[CH:22][N:23]=1)[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][CH2:17][N:16]2[CH:26]([CH3:28])[CH3:27])[C:6](O)=[O:7].[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[C:15]2[C:21](=[CH:22][N:23]=1)[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][CH2:17][N:16]2[CH:26]([CH3:28])[CH3:27])[C:6]([NH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:7]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Reactant: NCCN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCN2CCCCC2)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the hydrochloride salt of 3-methoxy-4-[(2-methyl-3-oxo-6-propan-2-yl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-9-yl)amino]benzoic acid (Example 204; 127 mg, 0.33 mmol) and 1-(2-aminoethyl)piperidine (Aldrich, 54 uL, 0.38 mmol) and DIPEA (157 uL, 0.9 mmol) in anhydrous DMA (10 mL) at room temperature under nitrogen was added HATU (126 mg, 0.33 mmol) as a solid and the resulting solution stirred at room temperature overnight. The reaction mixture was loaded onto a SCX-3 column pre-wet with Methanol and the column washed with Methanol. The column was eluted with Ammonia in Methanol and product containing fractions evaporated. The resultant material was dissolved in dichloromethane and chromatographed with 2-5-10-20% methanol/dichloromethane followed by 7N ammonia/methanol. Evaporation of product containing fractions gave a yellow foam which was purified by reverse phase HPLC to yield the title compound as an off white gum (75 mg, 46%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=1)[CH3:2].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[C:10]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=1)[CH3:2]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)CCC(=O)c1ccc(O)c(CCC(=O)OCC)c1
Product: CCOC(=O)CCC(=O)c1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Yield: 80.6 %

Procedure:
Starting with 0.458 g (1.42 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-hydroxy-γ-oxobenzenebutanoic acid ethyl ester, and 1.65 g (7.29 mmol) of 1,5-dibromopentane, the title compound was obtained in 80.6% yield as a white solid, mp 40°-41° C., using the procedure of example 21.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11]>O1CCCC1>[Br:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([N:2]([CH3:3])[CH3:1])=[O:11]
Reactant: O=C(Cl)CCCCCBr
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCCCBr
Yield: 89.7 %

Procedure:
A solution of 27.5 g (0.610 mole) of dimethylamine in 100 ml of cold tetrahydrofuran was added dropwise to a solution of 25.0 g (0.117 mole) of 6-bromohexanoyl chloride in 100 ml of tetrahydrofuran. The reaction mixture was stirred mechanically and the temperature maintained between 5° and 15° C. throughout the addition. After the final addition, the solution was filtered to remove the solid precipitate and the filtrate was concentrated under reduced pressure to yield 23.3 g (90%) of light-yellow oil. An analytical sample was prepared by filtering the oil through a small bed of silica gel and eluting with ethyl acetate. The fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4](OCC)=[O:5].O.[NH2:22][NH2:23]>C(O)(C)C>[NH2:1][C:2]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4]([NH:22][NH2:23])=[O:5]
Reactant: CCOC(=O)c1c(C(F)(F)F)cc(C(F)(F)F)nc1N
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: NNC(=O)c1c(C(F)(F)F)cc(C(F)(F)F)nc1N
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-amino-4,6-di(trifluoromethyl)-nicotinate (2.55 g., 8.45 mmole), 85% hydrazine hydrate (5 ml.) and isopropanol (5 ml.) is stirred in an oil-bath at 110° C. for 3 hours. On cooling, the dark red solution deposits colorless crystals which are filtered off and washed with a little isopropanol. A second crop of solid is obtained by evaporation of the mother liquors giving a total yield of 1.45 g. (59.6%) of product, m.p. 240°- 243° C. (dec.). Upon recrystallization from isopropanol (25 ml.) there is obtained 1.05 g. (42.8%) of product, m.p. 244°-245° C. (dec.).
Reaction SMILES: [Br:1][C:2](=[O:7])[CH:3](Cl)[CH2:4][CH3:5].[NH:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[Br:1][C:2](=[O:7])[CH:3]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:8][C:9](=[O:10])[CH2:11][CH2:12]2)[CH2:4][CH3:5]
Reactant: CCC(Cl)C(=O)Br
Reactant: O=C1CCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCC(C(=O)Br)c1ccc2c(c1)CCC(=O)N2

Procedure:
A solution of α-bromobutanoyl chloride (78.9 g) in methylene chloride (50 ml) is added to a stirred mixture of 3,4-dihydrocarbostyril (31.3 g) and aluminum chloride (59.6 g) in methylene chloride (300 ml). The reaction mixture is stirred at reflux for about 3.5 hours, cooled, poured into a mixture of ice and water, resulting in the formation of a white precipitate which is filtered, washed with water, dried, and recrystallized from isopropanol, affording the desired product.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]1([CH3:20])[CH2:19][O:18]1)(=[O:12])[CH3:11].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:20][C:17]([OH:18])([CH3:19])[CH2:16][CH2:15][CH2:14][O:13][C:10](=[O:12])[CH3:11])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC(=O)OCCCC1(C)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)OCCCC(C)(O)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 79.1 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (6.8 g, 43 mmol), 2-(3-acetoxypropyl)-2-methyloxirane (5.8 g, 39.3 mmol) and sodium acetate (3.9 g, 47.6 mmol) were suspended in ethanol (60 ml) followed by stirring under reflux overnight. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to afford 2-chloro-l-(5-acetoxy-2-hydroxy-2-methylpentyl)-4-nitroimidazole (9.5 g, yield 79%) as a light brown oil.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][SiH:10]([Cl:12])[Cl:11]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([Si:10]([Cl:12])([Cl:11])[Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCc1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 83.1 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.23 g (0.78 mmol) of tetrabutylphosphonium chloride, 1.00 g (7.90 mmol) of benzyl chloride, and 3.21 g (23.7 mmol) of trichlorosilane were reacted at 130° C. for 4 hrs. The resulting mixture was distilled to give 1.48 g of benzyltrichlorosilane (yield; 83%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]([Cl:11])=[N:4][N:3]=1.[CH2:12]([O:14][C:15]([C:17]1N=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][C@@H:25]([CH3:29])[CH2:24]2)=[N:21][CH:22]=1)=[O:16])C.[CH2:30](N(CC)CC)C.O>CN1C(=O)CCC1.CCOC(C)=O>[CH3:12][O:14][C:15](=[O:16])[C:17]1[CH:30]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[C:7]4[CH2:8][CH2:9][CH2:10][C:6]=4[C:5]([Cl:11])=[N:4][N:3]=3)[C@@H:25]([CH3:29])[CH2:24]2)=[N:21][CH:22]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cnc(N2CCN[C@@H](C)C2)cn1
Reactant: Clc1nnc(Cl)c2c1CCC2
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCN(c3nnc(Cl)c4c3CCC4)[C@@H](C)C2)nc1
Temperature: 195 °C
Yield: 16.3 %

Procedure:
To a solution of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (150 mg, 0.79 mmol) in NMP (5 mL) is added (S)-3-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid ethyl ester (297 mg, 1.19 mmol) and triethyl amine (332 μL, 2.39 mmol). The reaction mixture is heated in a microwave reactor at 195° C. for 4 h. Water and EtOAc is added. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (EtOAx/heptane 10% to 70%) to yield 50 mg (16%) of the title compound.
Reaction SMILES: Br.[CH2:2]([O:6][CH:7]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([O:11]CC)=O)[CH2:3][CH2:4][CH3:5].[O-:31][C:32]#[N:33].[K+].Cl>C(O)C.O>[CH2:27]([O:26][CH:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:32](=[O:31])[NH:33][C:9]1=[O:11])[CH2:28][CH2:29][CH3:30]
Reactant: N#C[O-]
Reactant: CCCCOC(OCCCC)C(NCCCCCCC(=O)OCC)C(=O)OCC
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCOC(OCCCC)C1C(=O)NC(=O)N1CCCCCCC(=O)OCC
Temperature: 100 °C
Reaction time: 22 h
Yield: 107.8 %

Procedure:
A mixture of 2-(dibutoxymethyl)glycine ethyl ester (2.0 g) with ethyl 7-bromoheptanoate (1.82 g) was heated under nitrogen in a bath at 100° C. for 3 hours. to give crude ethyl 7-((2,2-dibutoxy-1-ethoxycarbonyl-ethyl)amino)heptanoate hydrobromide. A stirred solution of 3.28 g of this hydrobromide in ethanol (13 ml) was cooled in ice-water and treated with a solution of potassium cyanate (1.34 g) in water (4ml), followed by 2N-aqueous hydrochloric acid (3.63 ml); the cooling bath was removed and stirring was continued at room temperature for 22 hours. The ethanol was evaporated in vacuo, the residue was shaken with water and ether, and the ethereal solution was separated, washed with water and dried over magnesium sulphate (MgSO4); removal of the ether left an oil which was heated under nitrogen at 100° C. for 3 hours, to give 5-dibutoxymethyl-1-(6-ethoxycarbonylhexyl)hydantoin (2.94 g). This was stirred in ether (6ml) with water (48 ml) and N-aqueous sodium hydroxide (24.9 ml) at room temperature for 11/2 hours and, after the addition of more ether (50 ml), the aqueous phase was separated, cooled (ice-H2O), stirred with fresh ether and acidified to Congo Red with N-aqueous hydrochloric acid. The ethereal solution of carboxylic acid was thrice washed with water, dried (MgSO4), and evaporated, to leave 1-(6-carboxyhexyl)-5-dibutoxymethylhydantoin (2.15 g) as a gum. When 1.89 g of the latter were cooled in ice-water and stirred with concentrated aqueous hydrochloric acid (8.5 ml), the resulting solution gave place spontaneously to a suspension of colourless crystals. The suspension was set at room temperature for 11/2 hours, diluted with water (10 ml) and set aside 15 minutes; the crystals were then collected, washed with water, dried in vacuo, suspended in ether (3 ml), and collected again, to give 1-(6-carboxyhexyl)hydantoin-5-carboxaldehyde (0.74 g), m.p. 223.5°-225° C. (Found: C.51.86; H, 6.66; N, 10.62. C11H16N2O5 required, C, 51.56; H, 6.29; N, 10.93%). In dimethyl sulphoxide-d6, this compound exists predominantly as the masked aldehyde, 1-(6-carboxyhexyl)-5-hydroxymethyl- enehydantoin.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.N1C=CC=CC=1.[OH-].[Na+]>CN(C)C(=O)C.[Cu]I.O>[CH:13]1([NH:16][C:2]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:15][CH2:14]1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: NC1CC1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1cc(F)c(F)cc1NC1CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
To a 10 ml resealable pressure reaction flask equipped with a magnetic stirrer and teflon septum cap was charged a solution of 1.0 g (5.19 mmol) 2-chloro-4,5-difluorobenzoic acid, 792 μl (11.43 mmol) cyclopropylamine, 800 mg (4.15 mmol) copper (I) iodide and 630 μl (7.79 mmol) pyridine in 8.0 ml of N,N-dimethylacetamide. The flask was sealed and was heated to 70° C. during stirring for a period of 16 hours. The reaction mixture was allowed to cool to room temperature and was then added to 100 ml of water. The suspension was adjusted to pH 13 with sodium hydroxide solution and was stirred for 15 minutes at room temperature. The suspension was filtered and the filtrate was adjusted to pH 4.5 with concentrated aqueous HCl. Filtration of the resulting slurry provided 451 mg (41%) of 2-cyclopropylamino-4,5-difluorobenzoic acid; m.p.: 175°-176° C.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:31])[C:14]([O:16][CH:17]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH2:18][CH3:19])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:31][CH:13]([CH3:12])[C:14]([O:16][CH:17]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH2:18][CH3:19])=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)C
Solvent: O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: CCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]propyl 2-methylpropanoate (575 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 30 (651 mg, 99% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 5H), 1.06 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.8 Hz, 3H), 1.17-1.39 (br. m, 3H), 1.64-1.76 (br. m, 4H), 1.83-1.91 (br. m, 2H), 2.09 (tt, J=12.4, 3.6 Hz, 1H), 2.50 (hept., J=6.8 Hz, 1H), 2.77-2.84 (br. m, 2H), 6.52 (t, J=5.6 Hz, 1H), 7.43 (t, J=6.0 Hz, 1H), 11.98 (br. s, 1H). MS (ESI) m/z 352.06 (M+Na)+; 328.02 (M−H)−.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[N:18][CH:19]=1.C(N(C(C)C)C(C)C)C.[Na+].[I-]>CN(C=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[N:18][CH:19]=1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Reactant: Fc1ccc(Br)cn1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccc(Br)cn1)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 120 °C

Procedure:
A mixture of 0.67 g (4 mmol) trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, 1.24 ml (12 mmol) of 5-bromo-2-fluoropyridine and 1.76 ml (13.6 mmol) N-ethyldiisopropylamine was heated for 3 h at 80° C. and 24 h at 120° C. The mixture was diluted with 1 ml DMF, treated with a catalytic amount of NaI and heated for 2 days at 120° C. The reaction was cooled, evaporated and partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (MeCl2/Et2O 97.5:2.5 to 92.5:7.5) gave 0.57 g (44%) of trans-3-{4-[(5-Bromo-pyridin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, MS: 323 (MH+, 1Br).
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:12]1[N:16]2[CH:17]=[C:18]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:32][CH2:31][CH:30]([C:33]([O:35]C)=[O:34])[CH2:29][CH2:28]4)=[N:25][CH:26]=3)[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH3:37])[CH3:11].O.[OH-].[Li+].C(O)(=O)C>C1COCC1.O>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:12]1[N:16]2[CH:17]=[C:18]([C:21]3[CH:26]=[N:25][C:24]([N:27]4[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]4)=[N:23][CH:22]=3)[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH3:37])[CH3:11]
Reactant: COC(=O)C1CCN(c2ncc(-c3ccc4nc(C)c(C(C)c5ccccc5OC(F)F)n4c3)cn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1nc2ccc(-c3cnc(N4CCC(C(=O)O)CC4)nc3)cn2c1C(C)c1ccccc1OC(F)F
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of Example 308 (0.28 g, 0.54 mmol) in THF (4 mL) at room temperature was added lithium hydroxide monohydrate (0.04 g, 0.81 mmol) in water (1 mL). The mixture was stirred for 2 h. The solution was adjusted to pH 6 by dropwise addition of acetic acid. The volatiles were removed in vacuo and the residue was treated with acetone (2 mL), causing a thick solid precipitate to form. The mixture was filtered and washed on the sinter with water and acetone, then dried in vacuo, to give the title compound (0.216 g, 79%) as a white solid. δH (400 MHz, DMSO-d6) 8.59 (s, 2H), 8.59 (s), 8.33 (s, 1H), 8.33 (s), 7.56 (dd, 1H, J 7.5, 1.3 Hz), 7.45 (m, 2H), 7.33 (m, 1H), 7.27 (m, 1H), 7.16 (d, 1H, J 8.1 Hz), 7.13 (t, 1H, J 78 Hz), 4.96 (m, 1H), 4.47 (m, 2H), 3.10 (m, 2H), 2.18 (m, 1H), 1.80 (m, 2H), 1.72 (m, 9H), 1.49 (m, 2H). LCMS (pH 3): MH+ 508.8, RT 1.77 minutes.