Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:42])[CH2:9][CH2:10][N:11]([CH2:13][CH:14]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([OH:36])=O)[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[N:15]1[CH3:41])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][O:44][CH:45]([O:53][CH3:54])[CH2:46][N:47]([CH3:52])[S:48]([NH2:51])(=[O:50])=[O:49].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:28]1([C:27]2[C:26]3[CH:25]=[CH:24][C:23]([C:34]([NH:51][S:48]([N:47]([CH2:46][CH:45]([O:44][CH3:43])[O:53][CH3:54])[CH3:52])(=[O:50])=[O:49])=[O:36])=[CH:22][C:21]=3[N:19]3[C:18]=2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[N:15]([CH3:41])[CH:14]([CH2:13][N:11]([CH3:12])[CH2:10][CH2:9][N:8]([CH3:42])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:20]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)CC1Cn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2N1C
Reactant: COC(CN(C)S(N)(=O)=O)OC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)C(=O)OC(C)(C)C)N(C)c1ccccc1-3)OC
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
6-{[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid, N-(2,2-dimethoxyethyl)-N-methylsulfamide (2 eq, Example 1, Step 1) and DMAP (5 eq) were dissolved in DCM (0.06M) and EDC (3 eq) was added. The mixture was warmed to 40° C. Within 5 min the clear yellow solution turned dark brown. The mixture was stirred overnight. After dilution with DCM the solution was extracted with 1N HCl, sat. aq. NaHCO3 and brine. After drying the organic phase over Na2SO4 the solution was discoloured with activated charcoal. All volatiles were evaporated in vacuo leaving tert-butyl {2-[({13-cyclohexyl-10-[({[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-amino)carbonyl]-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-6-yl}methyl)(methyl)amino]ethyl}methylcarbamate as a glassy brownish solid (MS (ES+) m/z 755 (m+H)+). The material was dissolved in DCM (0.03M) and water was added. To the biphasic system TFA was added and then the vigorously stirred mixture was warmed to 40° C. After 2 h the acetal was completely cleaved, while some N-Boc-protected material was still around. More TFA was added until a monophasic system was obtained. Heating was continued for 3 h. Then all volatiles were evaporated in vacuo and the residual material was coevaporated three times with toluene. The residual sticky material was digested with Et2O leaving a dark red powder. This material was used without further purification in the next reaction. (ES+) m/z 609 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12]C)[C:7]=1[CH2:14][CH2:15][CH3:16]>ClCCl>[F:5][C:6]1[C:7]([CH2:14][CH2:15][CH3:16])=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1
Reactant: CCCc1c(F)cccc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1c(O)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 559.8 %

Procedure:
24 ml (24 mmol) of a 1M boron tribromide solution in dichloromethane were added at -78° to a solution of 3.36 mmol (20 mmol) of 1-fluoro-3-methoxy-2-propyl-benzene in 25 ml of dichloromethane and the mixture was stirred for 10 minutes. After warming to room temperature the mixture was poured cautiously on to 100 ml of ice-water and extracted twice with 250 ml of dichloromethane each time. After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 4:1). There were obtained 2.9 g (94%) of 3-fluoro-2-propyl-phenol as a pale yellow oil.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[OH:9][C:10]1([CH3:18])[CH2:14][CH2:13][C:12](=O)[C:11]1([CH3:17])[CH3:16]>C(O)C.O>[OH:9][C:10]1([CH3:18])[CH2:14][CH2:13][C:12](=[N:7][OH:8])[C:11]1([CH3:17])[CH3:16]
Reactant: NO
Reactant: CC1(O)CCC(=O)C1(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(O)CCC(=NO)C1(C)C
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Sodium acetate (7.57 g, 92 mmol) and hydroxylamine hydrochloride (6.01 g, 87 mmol) were added to a solution of 3-hydroxy-2,2,3-trimethylcyclopentanone (8.20 g, 57.7 mmol, from Step 1) in ethanol (80 mL) and water (16 mL). The resultant mixture was heated to 80° C. for 15 h, then cooled to room temperature. After removal of ethanol in vacuo, the aqueous residue was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated to give crude 3-hydroxy-2,2,3-trimethylcyclopentanone oxime (9.05 g). 1H NMR (400 MHz, methanol-d4) δ ppm 2.29-2.80 (2 H, m), 1.63-1.94 (2 H, m), 1.22 (3 H, s), 1.08 (3 H, s), 0.99 (3 H, s).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3cccc(Cl)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(3-chloro-phenyl)-acrylic acid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][S:12][C:13]1[S:14][C:15]2[CH:21](O)[CH2:20][CH2:19][CH2:18][C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:30]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].[H-].[Na+].Cl>O1CCCC1.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][S:12][C:13]1[S:14][C:15]2[CH:21]([CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]([O:38][CH2:39][CH3:40])=[O:37])[CH2:20][CH2:19][CH2:18][C:16]=2[N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: OC1CCCc2nc(SCc3cccc(Oc4ccccc4)c3)sc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C1CCCc2nc(SCc3cccc(Oc4ccccc4)c3)sc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A mixture of 2-[(3-phenoxybenzyl)thio]-4,5,6,7-tetrahydro-1,3-benzothiazol-7-ol (2.00 g, 5.41 mmol), thionyl chloride (0.723 mL) and toluene (10 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was dissolved in tetrahydrofuran (10 mL). The solution was added to a mixture of diethyl malonate (1.60 g, 10 mmol), sodium hydride (60% in oil, 400 mg) and tetrahydrofuran (20 mL) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (AcOEt:hexane=1:19-2:1) to give the title compound (2.73 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:17][CH:16]([C:18]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>CCO.[Pd].CCOC(C)=O>[CH2:21]([NH:20][C:18]([CH:16]1[CH2:17][CH:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([F:1])[CH:3]=2)[CH2:15]1)=[O:19])[CH:22]([CH3:24])[CH3:23]
Reactant: [H][H]
Reactant: CC(C)CNC(=O)C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)C1CC(c2ccc(CN3CCCC3)c(F)c2)C1
Yield: 54 %

Procedure:
Crude intermediate 16, 3-(3-fluoro-4-((pyrrolidin-1-yl)methyl)phenyl)-N-isobutylcyclobut-2-enecarboxamide prepared above was dissolved in EtOH (100 mL) and added to a hydrogenation bottle containing 10% palladium on carbon slurried in EtOH (˜5 mL). The mixture was shaken at room temperature under 45 psi of hydrogen for 2 h, filtered through diatomaceous earth with an EtOH rinse and concentrated to yield an orange oil. This was dissolved in EtOAc (150 mL) and washed with aqueous K2CO3 and brine, dried over MgSO4 and concentrated to afford 3.29 g of waxy orange solid. Flash chromatography on a 2.5″×4″ silica gel column eluting with 1000 mL EtOAc and 500 mL 10% MeOH/EtOAc afforded 1.90 g (54%) of the title compound as a yellow tinged solid: Rf=0.26 (20% MeOH/EtOAc).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[N:6][CH:7]=1.Br[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]=3[N:22]([CH3:25])[C:23]=2[CH:24]=1>>[CH3:25][N:22]1[C:23]2[CH:24]=[C:16]([N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)=[CH:9][C:10]3=[O:14])[CH:17]=[CH:18][C:19]=2[C:20]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]1=2
Reactant: Cc1ccc(-c2cc[nH]c(=O)c2)nc1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)nc1
Yield: 64.7 %

Procedure:
4-(5-Methylpyridin-2-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (245 mg, 64%) as a yellow/green solid: 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.55-7.51 (m, 2H), 7.37 (d, J=1.6 Hz, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.10-7.03 (m, 2H), 4.66 (br m, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (br m, 2H), 2.42 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (0.23 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.081, 21%). MS (ISP) 471.5 [(M+H)+]; mp 218.5° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>O.CN(C)C(=O)C>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([C:31]2[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: N#Cc1ccc([C@@H](N)CC(=O)O)cc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc([C@H](CC(=O)O)NC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)cc1
Temperature: 150 °C
Yield: 90 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in an oven-dried flask with 3-(S)-Amino-3-(4-cyano-phenyl)-propionic acid (92 mg, 0.468 mmol) (commercially available from Combi-Blocks SS-1849) and N,N-dimethylacetamide (1.5 mL) was added with stirring. Solid sodium methoxide (25 mg, 0.468 mmol) was added and the reaction was heated to 150° C. in an oil bath for approximately five hours. The reaction was cooled and the solution diluted with five volumes of water. The solution was acidified to pH 3 with 1M hydrochloric acid to induce precipitation. Filtration of the solid followed by vacuum drying provided the desired product in 90% yield. LC-MS ESI−: 477 (M−1)−.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1.C(O)C(N)(CO)CO>ClCCCl>[CH3:1][C:2]1[C:7]([NH:8][S:29]([CH:26]2[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=S(=O)(Cl)C1CC1
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.6 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of cyclopropanesulfonyl chloride (38 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 9.7 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccc(F)cc2)cc1
Yield: 96.1 %

Procedure:
A mixture of methyl p-hydroxybenzoate (4.38 g, 28.8 mmol), p-fluorobenzyl chloride (5.0 g, 34.6 mmol) and anhydrous potassium carbonate (10 g) in acetone (250 ml) was heated under reflux for 24 h. The solid was then filtered and the filtrate was evaporated under reduced pressure. Crystallization of the residue from hexane gave 7.20 g (96%) of the title ester as white plates: mp 93-94° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.9 (3H, s, OCH3), 5.1 (2H, s, CH2), 7.0 (2H, d, J=8.8 Hz, aromatics), 7.11 (2H, m, aromatics), 7.43 (2 H, m, aromatics), 8.02 (2H, d, J=8.8 Hz, aromatics). Anal. Calcd for C15H13FO3: C, 69.22; H, 5.03. Found: C, 68.89; H, 4.69.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[C:33]([O:37][C:38](=[O:44])[C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)([CH3:36])([CH3:35])[CH3:34]>C(N(CC)CC)C.CN(C)C=O.O1CCCC1>[C:33]([O:37][C:38](=[O:44])[C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4.46 g. of carbobenzoxy-β-alanine is dissolved in 20 ml. of tetrahydrofuran and the resulting solution cooled to -10° C. With constant stirring of the solution, 2.4 ml. of N-methylmorpholine followed by 2.6 ml. of isobutylchloroformate are added and the resulting reaction mixture is stirred thereafter for approximately 5 minutes at -10° C. 4.16 g. of L-proline t-butyl ester hydrochloride in 20 ml. of dimethylformamide and 2.8 ml. of triethylamine is added to the reaction mixture which is thereafter stirred overnight, while slowly warming to room temperature. The solvent of the reaction mixture is evaporated in vacuo at 30°-35°. The residue is dissolved in 800 ml. of ethyl acetate which is washed with (2×150 ml.) a 10% citric acid solution, with (1×150 ml.) water, with (2×150 ml.) saturated solution of sodium bicarbonate and then with (2×100 ml.) water. The organic layer is dried with anhydrous magnesium sulfate and the solvent evaporated to yield carbobenzoxy-β-alanyl-L-proline t-butyl ester.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[C:9]([NH:11][C:12](=[O:15])[C:13]=1[CH3:14])=[O:10].C(N(CC)CC)C.CO>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([N:11]1[C:12](=[O:15])[C:13]([CH3:14])=[C:8]([CH3:7])[C:9]1=[O:10])=[O:3])[CH3:6]
Reactant: CC1=C(C)C(=O)NC1=O
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)C(C)=C(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Ethyl chloroformate (1.5 ml, 15.6 mmol) was added dropwise to a stirred solution of 2,3-dimethylmaleimide (1.5 g, 12 mmol) and triethylamine (2 ml, 14 mmol) in dimethylformamide (10 ml) at 0-5° C. The reaction mixture was allowed to warm to room temperature and stand for 4 h. Methyl alcohol (10 ml) was added, diluted with chloroform (50 ml) and washed with water (3×20 ml). The chloroform solution was dried (Na2SO4) and concentrated in vacuum to give N-ethoxycarbonyl-2,3-dimethylmaleimide (yield 80%).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]([CH3:25])=O.[Al].N>CO>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:22])[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Reactant: CC(C)=O
Agent: N
Agent: [Al]
Solvent: CO
Product: CC(C)N1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 48 h

Procedure:
0.50 gram (1.8 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine (prepared in a manner described in the preceding example), 3.96 grams (68.1 millimoles) of acetone and 5 milliliters of methanol were warmed gently to start dissolution. To this was added 0.30 gram (11 millimoles) of aluminum bits and a catalytic amount (0.01 gram; 0.04 millimole) of mercuric chloride and the resulting mixture stirred for 2.5 hours. A TLC analysis of the reaction mixture showed presence of some but minor amount of product. The mixture was stirred for 48 hours. A TLC analysis at this time (1 percent methanol/99 percent chloroform saturated with ammonia) indicated consumption of the starting material with the formation of a new product which was determined by 1H NMR to be a 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-isopropylpiperidine product. The reaction mixture was filtered through a pad of celite and the solvent removed in vacuo to obtain a residue which after recrystallization from a minimum amount of hot acetonitrile and drying for 3.5 hours at 100° C./1 mm. Hg, was a white powder, m.p. 124°-126° C. The product had elemental analyses as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[O:12][C:13](S(C)=O)=[N:14][N:15]=3)=[CH:9][N:10]=2)[CH:7]=1.BrC1C=CC2N(C(C3OC(S(C)(=O)=O)=NN=3)=CN=2)C=1.[CH:38]([OH:41])([CH3:40])[CH3:39].[Cl-].[NH4+]>O.C(OCC)(=O)C.O1CCCC1.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[O:12][C:13]([O:41][CH:38]([CH3:40])[CH3:39])=[N:14][N:15]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: CS(=O)c1nnc(-c2cnc3ccc(Br)cn23)o1
Reactant: CC(C)O
Agent: CS(=O)(=O)c1nnc(-c2cnc3ccc(Br)cn23)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Oc1nnc(-c2cnc3ccc(Br)cn23)o1

Procedure:
A mixture consisting of 60 mg crude product of a mixture of 6-bromo-3-(5-methanesulfinyl[1,3,4]oxadiazol-2-yl)imidazo[1,2-a]pyridine and 6-bromo-3-(5-methylsulfonyl[1,3,4]oxadiazol-2-yl)imidazo[1,2-a]pyridine obtained in the synthesis process in Production Example 280, 2 mL isopropyl alcohol, 0.3 mL triethylamine and 3 mL anhydrous tetrahydrofuran was heated overnight under reflux. An aqueous saturated ammonium chloride solution, ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 33 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl-].[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[C:35]12[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)[CH2:42]2)[C:29](O)=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C.CCCCCC>[CH2:10]([O:9][C:7]1[CH:6]=[CH:5][C:3]([NH:4][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([C:35]34[CH2:36][CH:37]5[CH2:38][CH:39]([CH2:40][CH:41]([CH2:43]5)[CH2:42]3)[CH2:44]4)=[C:26]([O:25][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:27]=2)=[C:2]([NH2:1])[CH:8]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1N
Reactant: O=C(O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OCc2ccccc2)c1
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1cc(OCc2ccccc2)ccc1NC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OCc2ccccc2)c1

Procedure:
2.7 g (12.7 mM) of 2-amino-4-(benzyloxy)aniline and 5 g (12.7 mM) of the chloride of 3-benzyloxy-4-(1-adamantyl)benzoic acid are treated under the conditions described in Example 1(f) to lead, after the same treatment andchromatography on silica in the ethyl acetate/hexane (30/70) eluent, to 4.2g (59.3%) of the expected derivative, of melting point 178° C.