Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH:11]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13][N:12]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O.[OH-].[Na+]>O>[CH2:24]([N:12]1[CH2:13][CH2:14][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH:11]1[CH2:9][OH:8])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
To the suspension of lithium aluminum hydride (1.54 g, 40.6 mmol) was added 1,4-dibenzyl-piperazine-2-carboxylic acid methyl ester (3.00 g, 9.25 mmol) portionwise at room temperature. The reaction mixture was stirred at reflux for 3 hours. After cooled to 0° C., 1.5 ml of water, 1.5 ml of 4N NaOH aq., and 4.5 ml of water was added successively. The mixture was stirred for 1 hour, and the white precipitate was filtered off with celite pad. The filtrate was concentrated in vacuo to give (1,4-dibenzyl-piperazin-2-yl)-methanol (2.74 g, quant.) as a yellow oil: HPLC-MS (ESI): Calcd for C19H24N2O[M+H]+297, found: 297.
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].N([O-])=O.[Na+].[C-:22]#[N:23].[K+]>Cl>[C:22]([C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])#[N:23]
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Product: N#Cc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]

Procedure:
i. 3-(4-Amino-3-nitrobenzoyl)propionic acid was diazotised in aqueous hydrochloric acid with sodium nitrite and the resultant solution treated with cuprous cyanide in potassium cyanide solution to give 3-(4-cyano-3-nitrobenzoyl)propionic acid, also available by a cyanide displacement reaction of 3-(4-fluoro-3-nitrobenzoyl)propionic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[C:13]3[N:14]([C:17]4[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=4)[N:15]=[CH:16][C:12]=3[CH2:11][CH2:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[N:33]1([C:21]([C:20]2[CH:19]=[CH:18][C:17]([N:14]3[C:13]4[C:7]5[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=5[CH2:10][CH2:11][C:12]=4[CH:16]=[N:15]3)=[CH:25][CH:24]=2)=[O:23])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: C1COCCN1
Reactant: CC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccc(C(=O)O)cc1)CC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccc(C(=O)N3CCOCC3)cc1)CC2
Reaction time: 0.25 h

Procedure:
A solution of 3.5 mg (0.01 mmol) 4-(7-acetylamino-4,5-dihydro-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-benzoic acid (prepared analogously to Example 1) in 0.5 ml DMF is combined with 4 μL (0.03 mmol) triethylamine and 4 mg (0.01 mmol) O-pentafluorophenyl-1,1,3,3-tetramethyluronium hexafluorophosphate (PFTU) and stirred for 15 minutes. A solution of 1 mg (0.01 mmol) morpholine in 0.5 ml DMF is added to this mixture and it is shaken for 12 hours at ambient temperature. Then 3 mg polyamine resin HL (0.01 mmol, 200-400 mesh) are added and the mixture is shaken for a further 8 hours. The resin is filtered off and the filtrate is evaporated to dryness in vacuo.
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:21]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:20][C:10]=1[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:23]=[CH:22][C:21]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:20][C:10]=1[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Yield: 95.5 %

Procedure:
10.8 g of t-butyl N-[2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl]carbamate was dissolved in 300 ml of ethanol, 2 g of 10% palladium-carbon was added thereto, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give 8.2 g of the title compound.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[C:22]3C=[CH:40][CH:41]=[CH:42][C:21]=3N(C3C=CC=CC=3)[C:19]2=O)=[CH:9]1)=O)(C)(C)C.[H-].[Na+].CI.[CH3:54][N:55]([CH:57]=[O:58])[CH3:56]>>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:19])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:36]([CH3:38])[CH3:37])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:21]=[CH:42][CH:41]=[CH:40][C:54]=3[N:55]([C:56]3[CH:18]=[CH:17][CH:10]=[CH:11][CH:12]=3)[C:57]2=[O:58])=[CH:9]1
Reactant: CN(C)C=O
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2c[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 210 mg (0.32 mmol) of 2-[3-(N-tert-butoxycarbonyl-indol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 38, in 4 mL of DMF at 0° C. is added 19 mg (0.48 mmol, 1.5 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 5 min, then 30 mL (0.48 mmol, 1.5 equiv) of methyl iodide is added. The reaction mixture is stirred 2 h at RT and then heated to 50° C. for 14 h, then quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. The crude material is then dissolved in 2 mL of dichloromethane, 2 mL of TFA is added, and the reaction mixture is stirred 1 h at RT. The volatiles are removed in vacuo and the resulting crude oil purified via MPLC using a Si60 silica gel column and hexane/EtOAc 5/2 as eluent followed by lyophilization afforded 37 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ8.11 (s, 1H), 7.61-7.00 (m, 18H), 6.76 (d, 1H, J=5.1), 5.10 (m, 1H), 4.50 (d, 1H, J=16.4), 3.95 (d, 1H, J=16.4), 2.91 (dd, 2H), 1.58 (s, 3H), 1.14 (m, 6H); low resolution MS (FAB)m/e 571 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[F:20][C:21]1[CH:22]=[C:23]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=C1CCCc2cc(-c3ccc(F)c(F)c3)ccc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3,4-difluorophenyl boronic acid according to the coupling procedure as described in example 6. MS (ESI) m/z 259.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27].ClCCl>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:27]#[C:26][CH2:25][OH:28])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(I)c21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cccc(C#CCO)c21

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.21 g) from Preparation No. 48, copper iodide (0.029 g), bis(triphenylphosphine)palladium(II) chloride (0.012 g), and propargyl alcohol (0.035 mL) in diethylamine (15 mL) is stirred at room temperature for 18 h. Dichloromethane followed by hexanes is added to the reaction mixture. The resulting solid is filtered, washed thoroughly with hexanes, and dried. The solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1 L), 0.5% MeOH:CH2Cl2 (1 L), 1% MeOH:CH2Cl2 (1 L), 1.5% MeOH:CH2Cl2 (1 L), 2% MeOH:CH2Cl2 (1 L), 3% MeOH:CH2Cl2 (1 L)) affords the title compound as a yellow solid (0.13 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=3[N+:25]([O-])=O)=[N:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].O1CCCC1>[NH2:25][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)=[N:12][N:13]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(C)(C)c1ccc(-c2nnc(-c3ccc(C(=O)O)cc3[N+](=O)[O-])o2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nnc(-c3ccc(C(=O)O)cc3N)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A mixture of 4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]-3-nitrobenzoic acid (0.200 g), 5% palladium on carbon (0.200 g) and tetrahydrofuran (20 ml) was stirred under a hydrogen atmosphere at room temperature and normal pressure for 30 min. Palladium on carbon was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1, volume ratio) to give 3-amino-4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (0.120 g, yield 67%). Recrystallization from hexane-ethyl acetate gave yellow prism crystals. melting point: 266–268° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:13][CH2:14][C:15]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)=[O:16]
Reactant: O=C1CCc2cccc(O)c2N1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCc2c(C(=O)CCl)ccc(O)c2N1
Temperature: 0 °C
Yield: 22.4 %

Procedure:
24.3 g of 8-hydroxy-3,4-dihydrocarbostyril (VII) and 68 g of chloroacetyl chloride were added to 130 ml of carbon disulfide, and 200 g of aluminum chloride was added slowly to the mixture while stirring and cooling in ice-water. The mixture was stirred for 6 hours at a temperature of 60° to 70°C and carbon disulfide was distilled off. The resulting residue was poured into 500 ml of ice-water. The precipitated crystals were filtered, washed with water and recrystallized twice from methanol to give 8.0 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril (IV) as light yellow crystals having a melting point of 189° to 191°C.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C@@H:6]1[CH2:12][CH2:11][C@H:10]2[C@H](O2)C1)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)S)C=CC=CC=1.[C:35](#[N:37])C>>[CH2:12]1[CH2:6][N:5]2[C:10](=[N:37][CH2:35][CH2:2][CH2:3]2)[CH2:11]1
Reactant: CC#N
Reactant: O=C(N[C@@H]1CC[C@@H]2O[C@@H]2C1)C(F)(F)F
Agent: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C1CN=C2CCCN2C1

Procedure:
1.55 g of 2,2,2-Trifluoro-N-(1R,3R,6S)-7-oxa-bicyclo[4.1.0]hept-3-yl-acetamide (Example 3 Step B), 2.46 g of triphenylmethanethiol and 25 mL of acetonitrile were charged to a flask. To the mixture obtained 880 μL of DBN was added, and the mixture obtained was heated to 60° C. and stirred for 23 h. Upon completion of the reaction (TLC), the mixture obtained was cooled to rt, diluted with EtOAc and washed with H2O and brine. The organic layer obtained was dried over MgSO4, concentrated in vacuo and the crude product obtained was subjected to column chromatography (eluent: Cyclohexane/EtOAc 5:1). The required fractions were identified, combined and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[N:18]=[N:19][N:20]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=3)[N:7]=2)[CH:3]=1.[Cl:41]N1C(=O)CCC1=O>>[Cl:41][C:5]1[N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[N:18]=[N:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=2)[N:7]=[C:8]2[C:4]=1[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2nn(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2c1
Product: Cc1ccc2nn(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Cl)c2c1

Procedure:
By treating 5-[2-(5-methyl-2H-indazol-2-yl)phenyl]-2-(triphenylmethyl)-2H-tetrazole as obtained in Reference Example 8, in the same manner as in Reference Example 4 by using N-chlorosuccinimide (1 equivalent amount) in place of N-bromosuccinimide, 5-[2-(3-chloro-5-methyl-2H-indazol-2-yl)-phenyl]-2-(triphenylmethyl)-2H-tetrazole was obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[N:36]=[C:37](SC)SC>CN(C=O)C>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]1[O:11][C@:3]2([CH2:2][N:1]=1)[CH:8]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:9]1)[CH2:4]2
Reactant: CSC(=Nc1nc2ccccc2o1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2oc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 10 ml-vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HCl salt (69.5 mg, 0.361 mmol), DMF (2 ml), DIEA (0.063 mL, 0.361 mmol) and Cs2CO3 (235 mg, 0.722 mmol) at room temperature, followed by dimethyl benzo[d]oxazol-2-ylcarbonimidodithioate (86 mg, 0.361 mmol). The resulting suspension was stirred at room temperature for 1 hr. LC/MS then indicated consumption of starting material. The mixture was diluted with MeOH and purified by preparative HPLC to afford the expected product, (R)—N-(benzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (101.5 mg, 0.323 mmol, 90% yield), as a tan gum. 1H NMR (400 MHz, Acetone-d6) δ ppm 2.07-2.14 (m, 2H) 2.20 (ddd, J=8.78, 5.27, 3.26 Hz, 2H) 2.33-2.45 (m, 1H) 2.62 (d, J=2.26 Hz, 1H) 3.34-3.47 (m, 3H) 3.48-3.58 (m, 1H) 3.75-3.88 (m, 2H) 4.15 (d, J=10.54 Hz, 1H) 4.32 (d, J=10.54 Hz, 1H) 7.13-7.26 (m, 2H) 7.41 (td, J=3.70, 1.63 Hz, 1H) 9.24 (br, s, 1H). MS (LC/MS) R.T.=0.792, [M+H]+=299.17.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:13]([NH:15][CH:16]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:17]([C:19]1[O:20][CH2:21][CH:22]([C:24]([O:26][CH3:27])=[O:25])[N:23]=1)[OH:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:13]([NH:15][CH:16]([CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:17]([C:19]1[O:20][CH:21]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[N:23]=1)[OH:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1COC(C(O)C(CCc2ccccc2)NC(=O)C(CC(C)C)NC(=O)OCc2ccccc2)=N1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(C(O)C(CCc2ccccc2)NC(=O)C(CC(C)C)NC(=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 6 h
Yield: 32.8 %

Procedure:
A solution comprised of methyl 2-[2-(2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxy-4-phenylbutyl]-4,5-dihydrooxazole-4-carboxylate (0.036 g, 0.067 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then DBU (11.2 mg, 72.7 μmol) and bromotrichloromethane (14.6 mg, 73.7 μmol) were added. The mixture was stirred for 6 hours at room temperature and concentrated. The residue was dissolved in ethyl acetate (20 mL) and the solution was dried (MgSO4) and concentrated. The product was purified from the residue by flash chromatography eluting with 1:3 hexanes/ethyl acetate to provide methyl 2-[2-(2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxy-4-phenylbutyl]oxazole-4-carboxylate (12 mg, 0.022 mmol) as a white solid. MS(PCI) m/z=538 (M+1) 1H NMR (CDCl3): δ 0.8-1.05 (d, J=4 Hz, 6H), δ 1.55-1.70 (m, 3H), δ 2.00 (m, 1H), δ 2.40 (m, 1H), δ 2.69 (m, 2H), δ 3.99 (m, 3H) 4.45 (m, 1H), δ 5.17 (s, 2H), δ 5.78 (m, 1H, δ 7.01 (d, J=4 Hz 1H), δ 7.14-7.47 (m, 10H) 7.72(d, J=4 Hz, 1H), δ 8.40 (s, 1H). (C29H35N3O7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCl.CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:8][CH2:9][CH2:10][C:11](=[O:13])[C:6]=2[CH:7]=1
Reactant: O=C(O)CCSc1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCSc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
3-(4-Fluorophenylthio)propanoic acid (3 g, 15 mmol) was dissloved in dichloromethane (30 mL) and cooled to 0° C. in an ice bath. Oxalyl chloride (10 mL) was added slowly, dimethyl formamide (1 drop) was added and the reaction mixture was stirred at 0° C. for 0.5 hours. At which point the reaction was concentrated under reduced pressure to a residue, then resuspended in dichloromethane and cooled to 0° C. in an ice bath, Cs2 (1 mL) was added and AlCl3 (4 g, 15 mmol) was added slowly. The reaction mixture was then allowed to warm to room temperature and stirred over night. Ice chips and water (250 mL) were added and stirred. Concentrated hydrogen chloride was added until pH of 2, and extracted with dichloromethane (3×150 mL). Organics were combined, washed with brine (1×100 mL) and water (1×100 mL), dried (sodium sulfate), and concentrated to a yellow solid. The solid was purified by flash column chromatography on 100 g silica gel, eluting 10% ethyl acetate in hexanes to give 6-fluoro-2,3-dihydro-4H-1-benzothiopyran-4-one (2.55 g, 93%). 1H NMR (CDCl3, 300 MHz): δ7.80-7.76 (m, 1H), 7.27-7.23 (m, 2H), 7.15-7.09 (m, 1H), 3.23 (t, 2H, J=6.4 Hz), 2.97 (t, 2H, J=6.4 Hz) ppm.
Reaction SMILES: COC([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]2[C:16]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:20])=[CH:17][CH:18]=[C:7]2[CH2:6]1)=O.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][NH:21][C:19]([C:16]2[N:8]3[C:7]([CH2:6][NH:5][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9]3)=[CH:18][CH:17]=2)=[O:20])[CH:24]=1
Reactant: COC(=O)N1Cc2ccc(C(=O)NCc3cccnc3)n2Cc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10-(methoxycarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide (5 mmol) of Step B in methanol (50 mL) was treated with potassium carbonate and stirred at room temperature overnight. Water was then added to the solution and the pH adjusted to 6 with 6N hydrochloric acid. The solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate, and evaporated to dryness. The residual oil was triturated with ethyl acetate and hexane to yield the title compound as a powder.
Reaction SMILES: C([O-])(C)C.[NH2:5][C:6](=[N:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][S:15][CH2:16][CH2:17][NH:18][CH:19]=[N:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[N:13]=1)[NH2:7]>CO>[CH:25]1[C:24]([S:21](/[N:20]=[CH:19]/[NH:18][CH2:17][CH2:16][S:15][CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6]([NH2:7])=[NH:5])[S:10][CH:11]=2)(=[O:22])=[O:23])=[CH:29][CH:28]=[C:27]([Br:30])[CH:26]=1
Reactant: NC(N)=Nc1nc(CSCCNC=NS(=O)(=O)c2ccc(Br)cc2)cs1
Agent: CC(C)[O-]
Solvent: CO
Product: N=C(N)Nc1nc(CSCCN/C=N/S(=O)(=O)c2ccc(Br)cc2)cs1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
57.9 g of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide isopropanolate are dissolved in 87 ml of methanol at a temperature ranging between 40 and 50° C. The resultant solution is allowed to stand till a certain degree of turbidness fades away, then filtered and poured onto 550 ml of water at 0-5° C. for 4 hours under energic stirring. After the addition is completed, the mixture is stirred for further 4 hours at 0-5° C. and filtered. The filtrate is washed with abundant water and dried in vacuo at a temperature below 30° C. to yield 49.9 g of ebrotidine Form A.
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:33][CH3:34])=[C:19]([C:21]([CH3:32])([CH3:31])[CH2:22][C:23](N2CCOCC2)=[O:24])[CH:20]=1>C1COCC1>[CH:1]1([CH2:7][C:23](=[O:24])[CH2:22][C:21]([C:19]2[CH:20]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=2[O:33][CH3:34])([CH3:32])[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CCCCC1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(=O)CC1CCCCC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of cyclohexylmethyl bromide (0.26 g) in THF (1 mL) cooled to −70° C. under argon, tert-butyl lithium (1.7 M in pentane, 1.8 mL) was added dropwise over 5 minutes. The mixture was stirred at −70° C. for 30 minutes. A solution of 3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.33 g) in THF (1 mL) was added all at once and the mixture was stirred for one hour. The reaction temperature rose to approximately −20° C. The reaction was quenched with EtOH (0.3 mL) and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, dried, filtered, and evaporated. Chromatography of the residue over silica gel (eluent:hexanes to methylene chloride gradient) gave the title compound as an oil (0.2 g).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]2=[O:13])[CH2:3][CH2:2]1.O[C@H:15]1[CH2:18][C@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(=O)(O)[O-].[Na+]>[CH:1]1([N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C@H:15]3[CH2:18][C@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:16]3)[C:5]2=[O:13])[CH2:3][CH2:2]1
Reactant: O=c1[nH]c2ncccc2n1C1CC1
Reactant: O=C(N[C@H]1C[C@H](O)C1)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3cccnc32)C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Cyclopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.740 g, 4.22 mmol), benzyl (trans-3-hydroxycyclobutyl)carbamate (0.934 g, 4.22 mmol), and triphenylphosphine (1.661 g, 6.33 mmol) were mixed in THF (15 mL) under an argon atmosphere and cooled to 0° C. Diisopropyl azodicarboxylate (1.244 mL, 6.33 mmol) was added dropwise via syringe, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield benzyl (trans-3-(1-cyclopropyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)cyclobutyl)carbamate (1.244 g, 3.29 mmol, 78% yield) as an off-white solid. M+1: 379.2.