Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][OH:5].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>>[CH:4]([OH:5])([OH:13])[CH2:3][CH2:2][CH3:1].[CH:12]([OH:13])([OH:5])[CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: OCCCCO
Reactant: OCCCCCCO
Product: CCCC(O)O
Product: CCCCCC(O)O

Procedure:
First, dimethyl terephthalate and 1,4-butanediol (the latter in an excess of 5-60, preferably 10-45, mol are reacted with one another at from 150° to 220° C. at from 0.7 to 1.5 bar for from 30 to 90, preferably from 40 to 70, minutes, transesterification taking place and the methanol formed, together with excess butanediol and small amounts of oligomeric and polymeric compounds and residual amounts of dimethyl terephthalate, being transferred with the vapors to a column into which a liquid residue containing dihydroxy compounds, as obtained, for example, in the distillation of 1,4-butanediol or 1,6-hexanediol, is simultaneously introduced. The composition of the residue is not subject per se to any particular restriction, provided that it is in liquid form and no compounds which interfere with the separation in the column are present. This is generally the case for the residues described, which are obtained from the distillation of butanediol and hexanediol.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:37]1[S:38][C:39]2[C:44](=[O:45])[NH:43][N:42]=[CH:41][C:40]=2[N:46]=1.C(O)(C)C>C(N(CC)CC)C>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:37]3[S:38][C:39]4[C:44](=[O:45])[NH:43][N:42]=[CH:41][C:40]=4[N:46]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[O:11])=[CH:32][CH:33]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=c1[nH]ncc2nc(Cl)sc12
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3cn[nH]c(=O)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Yield: 92.7 %

Procedure:
To a mixed solution of the compound (26 mg) obtained in Example 783, the compound (10 mg) obtained in Step 6 and isopropanol (1.0 ml) was added triethylamine (14 μl) at room temperature, and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:20, developed twice) to give the title compound (31 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1.C1N=C[N:31](C(N2C=NC=C2)=O)[CH:30]=1.CN>CN(C=O)C.C(Cl)Cl>[CH3:30][NH:31][C:26]([C:24]1[S:25][C:21]([C:19]2[O:18][N:17]=[C:16]([C:4]3[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]([CH3:15])[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:5]=3)[N:20]=2)=[CH:22][CH:23]=1)=[O:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)O)s3)n2)n1
Agent: CN
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-thiophene-2-carboxylic acid (Intermediate 62, 316 mg, 0.80 mmol) in anhydrous DMF (4 mL) was added CDI (190 mg, 1.17 mmol). The mixture was stirred for 2 h and then heated at 50 C for 3 h. After this time more CDI (190 mg, 1.17 mmol) was added and the mixture heated at 65 C for 18 h. After cooling to room temperature, methylamine (2 M in THF, 3.5 mL, 7 mmol) was added and the mixture stirred at room temperature for 1 hr The reaction mixture was then diluted with DCM (20 mL), extracted with aqueous sodium hydroxide solution (1M, 20 mL), saturated brine (20 mL) and dried over sodium sulfate. Evaporation of the solvent gave an orange gum which was purified by preparative HPLC (Method A) and then by chromatography on silica eluting with 4% MeOH-DCM to give the title compound (27 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH2:14][C:15]1([NH2:19])[CH2:18][O:17][CH2:16]1.C(N(CC)CC)C>CO>[NH2:19][C:15]1([CH2:14][NH:13][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:18][O:17][CH2:16]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NCC1(N)COC1
Solvent: CO
Solvent: CCN(CC)CC
Product: NC1(CNc2nc(Cl)nc3ccccc23)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of 2,4-dichloroquinazoline (1.0 g, 5.024 mmol) in methanol (15 mL) was added 3-(aminomethyl)oxetan-3-amine (855 mg, 60%, 5.024 mmol) and triethylamine (101 mg, 1.005 mmol). After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography to afford 1.2 g of the desired product as a white solid (yield was 92%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(Cl)c1ccccc1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)c1ccccc1
Yield: 55 %

Procedure:
Using the general method of Example 47, benzoyl chloride (56 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.11 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]benzamide as a white solid. Analysis: Calculated for C24H28N6O+¼H2O: %C, 68.47; %H, 6.82; %N, 19.96. Found: %C, 68.24; %H, 6.76; %N, 19.90.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:41])[C@@H:12]([NH:21][C:22](=[O:40])[CH:23]([NH:32][C:33](OC(C)(C)C)=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.O=C(Cl)OC(Cl)(Cl)Cl>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:41])[C@@H:12]([N:21]2[C:22](=[O:40])[CH:23]([C:24]3[CH:25]=[CH:26][C:27]([S:30][CH3:31])=[CH:28][CH:29]=3)[NH:32][C:33]2=[O:34])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)C(NC(=O)OC(C)(C)C)c2ccc(SC)cc2)[C@@H](C)c2ccccc2)n1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(SC)cc3)C2=O)n1
Reaction time: 0.33 h

Procedure:
2-{(2S,3S)-2-[2-tert-Butoxycarbonylamino-2-(4-methylsulfanyl-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (110 mg, 0.18 mmol) was dissolved at 0° C. in a 30% solution of trifluoroacetic acid in dichloromethane. After 2.5 hours the reaction mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The aqueous layer was adjusted to pH=8 by the addition of solid sodium bicarbonate and then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to an off white solid. The solid was dissolved in a solution of diisopropyl ethyl amine (0.16 mL, 0.92 mmol) in dichloromethane (5 mL) and the resulting solution was added in a dropwise manner to a 0° C. mixture of diphosgene (16 μL, 0.13 mmol) in dichloromethane (5 mL). The mixture was stirred for 20 minutes and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated to the crude product. After purification by chromatography over silica gel gradient eluted up to 3:2 ethyl acetate/hexanes and precipitation of the material obtained from chromatography from dichloromethane with excess hexanes, 2-{(2S,3S)-2-[4-(4-methylsulfanyl-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester, was isolated as a white amorphous solid (45 mg, 46%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([N:28]3[CH2:33][CH2:32][C@H:31]([NH:34][C:35]([C:37]4[NH:38][C:39]([CH3:44])=[C:40]([Cl:43])[C:41]=4[Cl:42])=[O:36])[C@H:30]([O:45][CH3:46])[CH2:29]3)[S:21][C:22]=2[C:23]([O:25]CC)=[O:24])=[N:16][CH:17]=1.Cl>O1CCCC1.C(#N)C>[Cl:42][C:41]1[C:40]([Cl:43])=[C:39]([CH3:44])[NH:38][C:37]=1[C:35]([NH:34][C@@H:31]1[CH2:32][CH2:33][N:28]([C:20]2[S:21][C:22]([C:23]([OH:25])=[O:24])=[C:18]([C:15]3[CH:14]=[N:13][C:12]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:17][N:16]=3)[N:19]=2)[CH2:29][C@@H:30]1[O:45][CH3:46])=[O:36]
Reactant: OCCN1CCCC1
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(Cl)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CO[C@H]1CN(c2nc(-c3cnc(OCCN4CCCC4)cn3)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
To a stirred solution of 2-(pyrrolidine-1-yl)ethanol (0.102 mL, 0.872 mmol) in dry tetrahydrofuran (20 mL) was added sodium hydride (70 mg, 1.771 mmol) at 0° C. The reaction mixture was heated to 80° C. After 10 min, ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 250 mg, 0.436 mmol) was added to the reaction mixture at 80° C. and further maintained at 80° C. for 10 min. After the completion of the reaction, the reaction mixture was cooled and carefully quenched by adding ice pieces. The aqueous layer was extracted with ethyl acetate (2×50 mL) to get rid of any organic impurities and discarded. The aqueous layer was acidified to pH=2 using 2N HCl solution and was extracted with 10% methanol/dichloromethane (2×100 mL). The organic layer was dried and concentrated under reduced pressure to yield the product. The obtained product was stirred in acetonitrile (10 mL). The solid was filtered and dried to obtain 120 mg (45%) of 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-{5-[2-(pyrrolidin-1-yl)ethoxy]pyrazin-2-yl}-1,3-thiazole-5-carboxylic acid as yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccn2cc(-c3ccc(C#CCCO)cc3)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccn2cc(-c3ccc(C#CCCOS(C)(=O)=O)cc3)nc2c1
Temperature: 10 °C
Yield: 66.4 %

Procedure:
The product of Step B (0.135 g) in dichloromethane (3 mL) was treated with pyridine (0.37 g) and cooled to 10° C. The cold solution was treated with methanesulfonyl chloride (0.112 g) and allowed to stir and warm to ambient temperature over 18 hours. The reaction mixture was washed with 1% H2SO4 solution, saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give the title compound (0.115 g).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([S:28]([N:31]=[CH:32][N:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C1COCC1.O>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([S:28]([N:31]=[CH:32][N:33]([CH3:34])[CH3:35])(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[CH:7]=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(SC)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(SC)cn1Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
5 g of 2-butyl 4-(methylthio)1H-imidazole is dissolved in 120 cm3 of THF. 1.55 g of 50% sodium hydride dispersed in oil is then added slowly to the orange-coloured solution obtained. The temperature is increased to 25° C. The reaction medium is agitated for 30 minutes at this temperature then 14 g of 4'-bromomethyl N-[(dimethylamino)methylene](1,1'-biphenyl)2-sulphonamide is introduced. Agitation is carried out at ambient temperature until evolution is complete, that is for about 3 hours. The resultant product is taken up in water, extraction is carried out with ethyl acetate, followed by separation by chromatography on silica, eluting with ethyl acetate then impasting in iso ether, filtration and drying. In this way 9.35 g of the expected product (colourless crystals) is obtained. M.p.=148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][N:13](C(OC)OC)C.CO>CN(C=O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][N:11]2[N:13]=[CH:12][N:1]=[C:2]2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccn2ncnc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of methyl 2-aminoisonicotinate (28.8 g, 191 mmol) in DMF (97.5 mL) was added DMF-DMA (70.6 mL, 496 mmol) and the mixture heated to 130° C. for 12 hours. The mixture was then concentrated to give a residue. To the residue was added MeOH (381 mL), followed by NH2OHSO4 (31.9 g, 248 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate in 18% yield, 6 g. To a solution of methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3 g, 16 mmol) in methanol was added 1M aq. LiOH (70 mL) and the resulting mixture stirred for 10 hours at room temperature. The pH was adjusted to 5-6 using aq. HCl and the whole mixture extracted with EtOAc (30 mL×3). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid in 38% yield, 1.05 g 1H NMR (400 MHz, DMSO-d6) δ: 7.56-7.58 (m, 1H), 8.32 (m, 1H), 8.66 (m, 1H), 9.04-9.06 (m, 1H), 13.5-14.0 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3](Br)([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])[CH2:4]Br.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C([O-])([O-])=O.[K+].[K+]>O>[F:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[CH:3]([CH2:4][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[CH2:2][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: Fc1ccc(C(Br)(CBr)CBr)c(F)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Fc1ccc(C(Cn2cncn2)Cn2cncn2)c(F)c1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
To a mixture of 1,2,3-Tribromo-2-(2,4-difluorophenyl)propane (5 g, 12.7 mmol) and water (25 ml), 1,2,4-Triazole (3.5 g, 50.8 mmol) and K2CO3 (3.5 g, 25.5 mmol) were added. The mixture was heated to reflux for 15-18 hours with vigorous stirring. The reaction mixture was cooled to room temperature and the product was extracted with EtOAc (3×100 ml). The combined EtOAc phase was washed with water and dried (Na2SO4). Evaporation of the solvent in vacuo and purification of the residue on a silica gel column with EtOAc and EtOH:EtOAc (1:19) as the elements, furnished the title compound (0.88 g, 23%).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13])=[O:22]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccc(C(F)(F)F)cc1O
Product: O=C(Nc1ccc(C(F)(F)F)cc1O)Nc1ccccc1Br
Yield: 66.6 %

Procedure:
The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171g, 1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.25 g, 54%). EI-MS m/z 375(M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[CH2:9])[C:5]([O:7][CH3:8])=[O:6].CO[CH2:12][N:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:8][O:7][C:5]([C:4]1([CH2:3][O:2][CH3:1])[CH2:9][CH2:12][N:13]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14]1)=[O:6]
Reactant: C=C(COC)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1(C(=O)OC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of methyl 2-(methoxymethyl)acrylate (176 mg, 1.35 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (416 μl, 1.63 mmol) in dichloromethane (2 ml) was added at 0° C. trifluoroacetic acid (21 μl, 0.27 mmol). The resulting solution was warmed to room temperature and stirred overnight. The crude product was purified by column chromatography on silica, eluted with a solution of ethyl acetate in hexanes (1:3), then 5% methanol in ethyl acetate to give the title compound (293 mg, 82%).
Reaction SMILES: [Na].CN(C)[C:4]1[CH2:8][CH2:7][CH2:6][N+:5]=1[CH3:9].COS([O-])(=O)=O.[CH2:17]([O:19][C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:18].O>C(O)C.CCOCC>[CH2:17]([O:19][C:20]([C:21](=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:28])[CH3:18]
Reactant: CN(C)C1=[N+](C)CCC1
Reactant: CCOC(=O)Cc1ccccc1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=C1CCCN1C)c1ccccc1

Procedure:
Add a solution of 6.9 g of sodium in 140 ml of ethanol dropwise at 90°, with stirring, in a stream of nitrogen, to 84 g of 2-dimethylamino-1-methyl-1-pyrrolinium-methylsulfate and 37.9 g of phenylacetic acid ethyl ester. Stir the thus-prepared reaction mixture for a further 30 minutes at 90° and then distribute it between water and diethyl ether (300 ml of each). Isolate the product from the ether phase and distil it to obtain a yield of 48 g (85% of theory) of title compound (b.p. 106° to 107° at 0.008 mm of Hg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(Cl)Cl>[NH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:2][NH:1][C:25](=[O:26])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:7]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
t-Butyl trans-4-aminomethylcyclohexylcarbamate (344 mg, 1.5 mmol) was dissolved in CH2Cl2 (7 mL) and cooled in an ice-bath. Triethylamine (0.21 mL, 1.5 mmol) was added, followed by benzyl chloroformate (0.22 mL, 1.5 mmol) dropwise. The mixture was stirred at rt under N2 for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with water and brine, dried over Na2SO4, filtered, and concentrated to a white solid. This solid was dissolved in 10 mL of 4 N HCl-dioxane and stirred at rt for 10 min. The solvent was removed. The residue was dried under vacuum to give 350 mg of the desired product as a white solid (78%). MS 263.36 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:13]([C:24]([O:26]CC)=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][OH:34]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.[Zn]>[C:24]([OH:26])(=[O:25])[CH3:13].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:13]([C:24]([O:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CN(C)CCO
Reactant: CCOC(=O)C1=C(Nc2ccccc2Cl)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: CN(C)c1ccncc1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: CC(=O)O
Product: CN(C)CCOC(=O)C1=C(Nc2ccccc2Cl)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 19.5 %

Procedure:
A solution of the compound (0.10 g, 0.24 mmol) of Example 15, 2-(dimethylamino)ethanol (0.40 mL, 4.0 mmol), 4-dimethylaminopyridine (0.010 g, 0.082 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.018 g, 0.019 mmol) in N,N-dimethylacetamide (2.0 mL) was stirred at 130° C. for 24 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC (aqueous ammonium acetate/acetonitrile as eluents) to afford the titled compound as solid (0.012 g, y. 11%).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].IC.[O:9]=[C:10]1[CH:24]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:23]2[N:22]=[CH:21][N:14]3[CH2:15][C:16](=[O:20])[CH2:17][CH2:18][NH:19][C:12]([C:13]=23)=[CH:11]1>CN(C=O)C>[CH3:1][CH:15]1[N:14]2[CH:21]=[N:22][C:23]3[CH:24]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:10](=[O:9])[CH:11]=[C:12]([C:13]=32)[NH:19][CH2:18][CH2:17][C:16]1=[O:20]
Reactant: CC(C)(C)OC(=O)CC1C(=O)C=C2NCCC(=O)Cn3cnc1c32
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC1C(=O)CCNC2=CC(=O)C(CC(=O)OC(C)(C)C)c3ncn1c32
Reaction time: 18 h

Procedure:
Cesium carbonate (214 mg, 0.66 mmol) and iodomethane (93 mg, 0.66 mmol) were added to a solution of tert-butyl (2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate (109 mg, 0.33 mmol, described in Intermediate 32) in DMF (5 mL). After 18 h, the mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=346 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([OH:7])=[O:6].F[C:18]1[CH:29]=[CH:28][C:21]2[C:22](=[O:27])[N:23]([CH3:26])[CH2:24][O:25][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:16][C@H:12]([O:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([O:1][C:18]2[CH:29]=[CH:28][C:21]3[C:22](=[O:27])[N:23]([CH3:26])[CH2:24][O:25][C:20]=3[CH:19]=2)[CH:10]=1)[C:5]([OH:7])=[O:6])[CH2:13][O:14][CH3:15]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Reactant: CN1COc2cc(F)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(C(=O)O)c1
Temperature: 160 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (175 mg, 0.77 mmol), 7-fluoro-3-methyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (141 mg, 0.77 mmol) and potassium carbonate (321 mg, 2.32 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 16 hours then reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), the aqueous layer acidified with 1M citric acid and extracted into ethyl acetate (2×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), and reduced in vacuo to give the desired compound as a brown oil (0.24 g). m/z 453 (M+H)+