Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([NH:14][C@H:15]([C:20]([NH:22][C@H:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21])[CH2:16][CH2:17][CH2:18][NH2:19])=[O:13].CN(C=O)C.[N+](C1C=CC(N[C:50](=[O:59])[O:51][CH2:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)=CC=1)([O-])=O.C(N(CC)CC)C>O>[CH:53]1([CH2:52][O:51][C:50]([NH:19][CH2:18][CH2:17][CH2:16][C@@H:15]([C:20]([NH:22][C@H:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21])[NH:14][C:12]([C:4]2[N:3]([CH3:2])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:13])=[O:59])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)OCC1CCCCC1
Reactant: Cn1c(C(=O)N[C@@H](CCCN)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCC2CCCCC2)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a mixture of tert-butyl (1R,2S)-2-({N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate hydrochloride (0.41 g) and DMF (4.0 ml) were added cyclohexylmethyl 4-nitrophenylcarbamate (0.28 g) and triethylamine (94 mg) under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture was added water (10 ml) under ice-cooling, followed by stirring at room temperature for 1 hour. The solid precipitated was collected by filtration, washed with water, and purified by silica gel column chromatography (chloroform/THF=10:1) to obtain tert-butyl (1R,2S)-2-({N5-[(cyclohexylmethoxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.41 g).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:4].CCN=C=NCCCN(C)C.C(N(CC)CC)C.[F:38][CH2:39][CH2:40][NH2:41]>ClCCl>[CH3:19][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:41][CH2:40][CH2:39][F:38])=[O:15])=[O:4]
Reactant: NCCF
Reactant: CN(C)C(=O)CCCC#Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCCC#Cc1cccc(C(=O)NCCF)c1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 3-(5-dimethylcarbamoyl-pent-1-ynyl)-benzoic acid (0.100 g, 0.38 mmol) in dry dichloromethane (1.5 mL) under a nitrogen atmosphere at room temperature, EDCI (0.0728 g, 0.38 mmol) was added followed by triethylamine (0.162 mL, 1.14 mmol), the resulting mixture was stirred at room temperature for further minutes. 2-Fluoro ethylamine (0.189 g, 1.9 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organic layer was separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 95% to 5% methanol gradient) to afford 3-(5-dimethylcarbamoyl-pent-1-ynyl)-N-(2-fluoro-ethyl)benzamide (26) (0.103 g, 0.34 mmol, 91% yield).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]([N:16]1[CH2:20]C2=C[S:22][CH:23]=[C:18]2[CH2:17]1)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7].ICC>CCCCCC.O1CCCC1>[CH2:3]([C:2]1[S:22][CH:23]=[C:18]2[CH2:17][N:16]([S:6]([C:9]3[CH:10]=[CH:11][C:12]([CH3:13])=[CH:14][CH:15]=3)(=[O:8])=[O:7])[CH2:20][C:1]=12)[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cscc3C2)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCI
Product: CCc1scc2c1CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.75 ml of a 1.6M solution of n-butyllithium in hexane are added, at -70° C., to a solution of 1.4 g of 5-tosyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole in 15 ml of dry tetrahydrofuran. 0.51 ml of iodoethane is then added and the mixture is stirred at room temperature for 2 h and the solution is then poured into 100 ml of ice-cold water. The solid formed is filtered off, washed with hexane and recrystallized from ethanol. 0.16 g of product is obtained. Melting point: 117°-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[O:35][C@H:18]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][CH:38]([O:41][CH3:42])[CH2:39][NH2:40].ClCCl>C(O)C>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]([C@H:18]([OH:35])[C@@H:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[NH:40][CH2:39][CH:38]([O:41][CH3:42])[O:37][CH3:36])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(CN)OC
Reactant: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc([C@@H](NCC(OC)OC)[C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1

Procedure:
Mixture: 187.2 g (0.4 mol) of rel-(S,S)-3,3'-dibenzyloxy-4,4'-dimethoxystilbene oxide, 210 g (2 mol) of aminoacetaldehyde dimethyl acetal, 5 l of dichloromethane, 3 l of ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5]2.[C:15](Cl)(=O)C(Cl)=O.CC1(C)OC(=O)CC(=O)O1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12](=[O:14])[CH3:15])[CH:6]=[CH:5]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cn1ccc2cc(Cl)ccc21
Agent: CC1(C)OC(=O)CC(=O)O1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Cn1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of acid from Step 1 (1.048 g, 5 mmol) in CH2Cl2 (45 mL) at r.t. there was added oxalyl chloride (762 mg, 6 mmol) and 2 drops of DMF. The mixture was stirred at r.t. for 1 hour, then it was added slowly to a cooled (0° C.) solution of 2,2-dimethyl-1,3-dioxan-4,6-dione (864 mg, 6 mmol) in CH2Cl2 (10 mL) and pyridine (1 mL). The resulting mixture was stirred at 0° C. for 30 minutes, then at r.t. for 1.5 hours. The CH2Cl2 was evaporated, there was added a mixture of HOAc (15 mL) and H2O (30 mL), and the mixture was heated at 90° C. for 45 minutes. After dilution with H2O, the mixture was extracted twice with EtOAc, and these combined extracts were washed with H2O, dried and evaporated to a residue which was chromatographed on silica gel, eluting with EtOAc-hexane (1:2) to afford the title compound as a yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:8]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:7]2[C:6]=1[OH:23])=[O:4].[NH2:24][CH2:25][C:26]([O-:28])=[O:27].[Na+]>>[Cl:22][C:20]1[CH:21]=[C:7]2[C:6]([OH:23])=[C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:8]2[CH:19]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2cccnc2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cn2n(Cc2cccnc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-pyridin-3-ylmethyl-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (5 eq.). ESI (m/z): 377 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[O:24]1[C:29]2[CH:30]=[CH:31][C:32](B(O)O)=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1>>[O:24]1[C:29]2[CH:30]=[CH:31][C:32]([C:6]3[N:7]=[C:8]([N:10]4[C:14]5[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=5[N:12]=[CH:11]4)[S:9][C:5]=3[C:3]([OH:2])=[O:4])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccc5c(c4)OCCO5)c(C(=O)O)s3)c2cc1OC
Yield: 21.6 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 1,4-benzodioxane-6-boronic acid (27 mg, 0.15 mmol) gave 4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (9.5 mg, 22%) as a white solid. MS 440 m/z (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][NH:7]1.Br[CH2:27][C:28](Br)=[O:29].[CH2:31]([O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37])[CH3:32]>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][N:7]1[CH2:27][C:28]([NH:37][CH2:36][C:35]1[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=1[O:33][CH2:31][CH3:32])=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(OC)c(CC2NCCc3c(OC)ccc(OC)c32)c1
Reactant: CCOc1ccccc1CN
Product: CCOc1ccccc1CNC(=O)CN1CCc2c(OC)ccc(OC)c2C1Cc1cc(OC)ccc1OC

Procedure:
prepared by reaction of 1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:22]([O:24]C)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH:8]=[CH:7]2)([O-])=O.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15])[CH:8]=[CH:7]3)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Product: CC(C)C[C@H](NC(=O)Cn1ccc2cc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ccc21)C(=O)O

Procedure:
The title compound was prepared from methyl N-[(5-nitro-1H-indol-1-yl)acetyl]-L-leucinate and 4-tert-butylphenyl sulfonyl chloride following the procedures of Example 10 Step 4 and Step 5: MS (ESI) m/z 500; MS (ESI) m/z 498.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS([C:26]([F:29])([F:28])[F:27])(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]1=[O:20].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[C:40](=O)([O-:42])[O-:41].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:26]([F:27])([F:28])[C:40]([OH:42])=[O:41].[Cl:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]1=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1N1CCOCC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C(F)(F)F
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1N1CCOCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid (R)-3,5-dichloro-4-(1-morpholin-4-yl-2-oxo-pyrrolidin-3-ylmethyl)-phenyl ester (0.126 g, 0.26 mmol), 4-fluorophenylboronic acid (0.044 g, 0.31 mmol), sodium carbonate (0.084 g, 0.79 mmol) in THF (10 mL) and water (3 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.015 g, 0.011 mmol) and then raise the reaction temperature to 80° C. and stir for 2 hours. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 50% ethyl acetate in hexanes to 100% ethyl acetate to afford 0.102 g (92%) of the titled product and then convert to the TFA salt by treating with trifluoroacetic acid. MS (m/z): 423 (M+).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH:9](Cl)Cl)[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-:19].[K+].CS(C)=O>O>[O:18]([CH:9]([O:19][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]1[N:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: [OH-]
Reactant: N#Cc1cccc(C(Cl)Cl)n1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Temperature: 60 °C

Procedure:
A mixture of 4.18 g of 6-cyano-2-(dichloromethyl)pyridine, 5.25 g of phenol, 3.33 g of potassium hydroxide and 50 ml of dimethylsulfoxide was heated to 60° C. After a reaction period of about 4 hours. the reaction was complete. The mixture was cooled and poured into 100 ml of water and then extracted with methylene chloride. The solvent extract was run through a bed of silica gel and the solvent removed. The mixture was heated to 160° C. at 0.05 milliliters of mercury. The resulting material was dissolved in a mixture of about 50 ml of methylene chloride filtered and the solvent removed by evaporation under reduced pressure. The above named product was recovered in a yield of 0.95 g and melted at 82°-85° C. The structure of the product was confirmed by its NMR and IR spectrum. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 74.44, 4.72 and 9.05 percent, respectively as compared with the theoretical contents of 75.50, 4.64 and 9.27 percent, respectively as calculated for the above named compound (Compound 28).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:18]#[N:19].[Na+].C(OCC)(=O)C.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:18]#[N:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](C#N)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of (R)-1-t-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (20 g) in dimethyl sulfoxide (200 ml) was added sodium cyanide (11 g) at ambient temperature under nitrogen. After stirring at 100° C. under nitrogen for 1 hour, the solution was taken up into a mixture of ethyl acetate and water. The organic layer was separated, and washed with water and brine successively. The dried solvent was evaporated, and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give (S)-1-t-butoxycarbonyl-3-cyanopyrrolidine (9.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:33][NH:34][O:35][CH3:36]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][C:10]([N:34]([O:35][CH3:36])[CH3:33])=[O:11])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: Cc1ccccc1C(CC(=O)O)c1ccc(Br)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.2 %

Procedure:
To a suspension of 3-(4-bromophenyl)-3-o-tolylpropanoic acid (125.5 g, 393 mmol) in dichloromethane (600 mL) was added 1,1′-carbonyldiimidazole (79.7 g, 491 mmol) portionwise over 5 min. After gas evolution had ceased N,O-dimethylhydroxylamine hydrochloride (42.2 g, 432 mmol) was added in portions over 5 min. The reaction mixture was stirred for 17 h at room temperature, then washed with water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The crude product was chromatographed (SiO2; heptane/ethyl acetate 3:1) and the product triturated with heptane to produce the title compound (127 g, 88%). White solid, MS: 362.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C@H:11]([C:13](=[O:18])N(OC)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C([Mg]Cl)(C)C.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C@@H:11]([CH3:12])[C:13]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: Clc1ccc(Br)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
[(S)-1-(Methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester (1 g, 3.8 mmol) and 4-bromochlorobenzene (0.9 g, 4.7 mmol) were dissolved in THF (10 mL). The solution was degassed with N2 for 5 minutes, and then cooled to 0° C. Isopropylmagnesium chloride (2M in THF; 4.7 mL, 9.4 mmol) was added slowly, and the reaction was stirred at room temperature for 2 hours. Once no starting material was seen by analytical tlc, the mixture was cooled to 0° C. 1N Aqueous HCl was added, and the organic layer was separated and washed with brine. After concentrating, the crude material was purified by silica gel chromatography to give the desired product as a colorless oil (1 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:36][CH2:37][O:38][CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:36][CH2:37][O:38][CH3:39])[CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COCCBr
Reactant: CCCCc1nc(C)n(-c2cccc(O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(OCCOC)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[4-butyl-1-(3-hydroxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.69 g) and 1-bromo-2-methoxyethane (0.43 mL) in N,N-dimethylformamide (7 mL) was added cesium carbonate (0.99 g), and the mixture was stirred at 70° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.69 g, 90%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(N(CC)CC)C.[CH:41]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH2:42]>>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:42][CH2:41][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(C)(=O)=O)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
To a solution of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) in IMS (industrial methylated spirits, 3 mL) was added triethylamine (0.20 mL, 1.47 mmol) and methyl vinyl sulfone (0.09 mL, 1.05 mmol) and the reaction mixture was stirred at RT (room temperature) for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (SiO2, 0-5% MeOH in DCM). Freeze-drying from methanol and water gave 320 as a pale yellow solid (135 mg, 68%). LCMS: RT=3.10 min, [M+H]+=474. 1H NMR δ (ppm) (DMSO-d6): 8.35 (1 H, d, J=8.19 Hz), 8.11 (1 H, s), 7.29 (1 H, d, J=8.27 Hz), 7.20 (1 H, s), 5.85-5.76 (1 H, m), 4.41-4.35 (3 H, m), 4.14 (3 H, d, J=59.98 Hz), 3.68 (2 H, s), 3.53-3.41 (3 H, m), 3.13 (3 H, s), 1.55 (6 H, d, J=6.60 Hz). 2 Protons obscured by water peak
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[F:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>O1CCCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:47][C:46]2[CH:48]=[CH:49][C:43]([F:42])=[CH:44][CH:45]=2)=[O:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
A mixture containing 4-acetyl-benzoic acid (4 g, 0.0243 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.13 g, 0.02673 mol), triethylamine (3.7 ml, 0.02673 mol), 1-hydroxybenzotriazole (3.62 g, 0.02673 mol) and 4-fluoroaniline (2.81 ml; 0.02916 mol) in 60 ml of tetrahydrofuran is stirred for 48 hours at 23° C. The reaction medium is filtered on frit and evaporated to dryness. The residue is taken up in a mixture of solvents : ethyl acetate-water: 50-50. The precipitate is filtered on frit, washed with isopropyl ether then isopentane. After drying, a white-coloured powder is obtained.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C.[ClH:23]>C(OCC)C.O1CCOCC1>[Cl-:23].[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][NH3+:15]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2ccccc2c1F
Reactant: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: [Cl-]
Product: [NH3+]CCOc1ccc2ccccc2c1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a cooled (0° C.) single necked flask containing a solution of tert-butyl {2-[(1-fluoronaphthalen-2-yl)oxy]ethyl}carbamate in 5 mL of ethyl ether, 5 mL of 4 M HCl solution in dioxane were added. The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduce pressure to afford 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride as a white solid (95% yield) which was pure by TLC and NMR analysis.