Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.[Br:11]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:11][C:2]1[CH:1]=[CH:6][C:5]2[NH:7][C:8](=[O:9])[O:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]c2ccccc2o1
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 63 h
Yield: 79.2 %

Procedure:
To a solution of benzoxazolinone (20 g, 0.148 mol) in 220 mL glacial acetic acid was added N-bromosuccinimide (NBS, 26.36 g, 0.148 mol), and the reaction mixture was stirred at room temperature for 63 hours before pouring into 1500 mL water. The precipitated product was washed thoroughly with water upon collection and recrystallized from EtOH to give 6-bromo-3H-benzoxazol-2-one (9) (25.09 g, 79%): Theory: C, 39.28; H, 1.88; N, 6.54; Br, 37.33. Found: C, 39.36; H, 2.02; N, 6.36; Br, 37.43. MP 192-194° C.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[NH:12]([C:14]([O:16]C)=O)[NH2:13].[CH3:18][O-].[Na+].O>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:16]=[C:14]1[NH:12][N:13]=[CH:18][N:10]1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:11]
Reactant: COC(=O)c1cccc(N)c1
Reactant: COC(=O)NN
Reactant: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-n2cn[nH]c2=O)c1
Reaction time: 2 h
Yield: 47.5 %

Procedure:
13 mmol of methyl-3-aminobenzoate were dissolved in 20 ml MeOH. 12 mmol of trimethylorthoformiate, 12 mmol methyl hydrazinocarboxylate and 50 mg of p-toluenesulfonic acid were added. The suspension was heated for 48 h to 65° C. 37 mmol of sodium methanolate were added and stirred for additional 2 h. The organic layer was reduced and water was added. The solution was acidified to pH=1 and the resulting solid filtered off to result in 5.7 mmol of product. MS(ISO): 204.2 (M−H+)
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH:5]#[CH:6].[C:7](Cl)(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(Cl)(Cl)(Cl)Cl>[Cl:1]/[CH:5]=[CH:6]/[C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [Cl-]
Reactant: C#C
Reactant: CCCCCC(=O)Cl
Agent: [Al+3]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(=O)/C=C/Cl

Procedure:
To a slurry of 233.5 g. (1.75 moles) of aluminum chloride in 390 ml. of carbon tetrachloride, saturated with acetylene and cooled in an ice bath, is added over 20 minutes 201.9 g. (150 moles) of hexanoyl chloride. After the addition is complete, acetylene is bubbled into the mixture is rapidly as it is absorbed and for 1 hour after absorption becomes slow. The mixture is poured onto 1700 g. of ice and 720 ml. of saturated brine. The organic phase is separated and the aqueous phase is washed with ether. The combined organic phase and washings are washed with saturated brine, dried (Na2SO4) and evaporated. The residual oil is combined with 10 g. of hydroquinone and distilled to yield a colorless oil, b.p. 51°-52° C. (0.10 torr.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([CH2:18][CH3:19])[N:17]=[C:4]2[CH:3]=1.[SH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:18]([C:16]1[N:17]=[C:4]2[CH:3]=[C:2]([S:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])=[CH:25][CH:26]=3)[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]2[CH:15]=1)[CH3:19]
Reactant: CCc1cn2c(Nc3cc(C)[nH]n3)nc(Cl)cc2n1
Reactant: O=C(Nc1ccc(S)cc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cn2c(Nc3cc(C)[nH]n3)nc(Sc3ccc(NC(=O)C4CC4)cc3)cc2n1
Temperature: 160 °C

Procedure:
7-chloro-2-ethyl-N-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-c]pyrimidin-5-amine 0.22 mmol, 0.06 g) was dissolved in DMF (1 mL). N-(4-mercaptophenyl)cyclopropanecarboxamide (0.24 mmol, 0.046 g) and K2CO3 (0.24 mmol, 0.033 g) was added. The reaction mixture was heated to 160° C. using a microwave reactor for 20 minutes. The mixture was then concentrated and purified by LC-MS to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83-0.84 (m, 4H) 1.25 (t, J=7.45 Hz, 3H) 1.79-1.86 (m, 1H) 2.12 (s, 3H) 2.73 (q, J=7.24 Hz, 2H) 5.80 (s, 1H) 6.65 (s, 1H) 7.58 (d, J=8.59 Hz, 2H) 7.81 (d, J=8.59 Hz, 2H) 8.31 (s, 1H) 10.55 (s, 1H) 10.97 (s, 1H) 12.30 (s, 1H); ESI-MS: m/z calc'd for C22H23N7OS 433.53; found 434.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[N:10]=[CH:9][NH:8][C:7](=[S:11])[CH:6]=1.Br[CH2:15][CH2:16][CH:17]([F:22])[C:18]([Br:21])([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:21][C:18]([F:20])([F:19])[CH:17]([F:22])[CH2:16][CH2:15][S:11][C:7]1[CH:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:12])[F:13])[N:10]=[CH:9][N:8]=1
Reactant: FC(F)(F)COc1cc(=S)[nH]cn1
Reactant: FC(CCBr)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(CCSc1cc(OCC(F)(F)F)ncn1)C(F)(F)Br
Temperature: 25 °C
Reaction time: 7 h
Yield: 53.5 %

Procedure:
6-(2,2,2-trifluoroethoxy)-4(3H)-pyrimidinethione (see Example 1B) (3 g) and 1,4-dibromo-3,4,4-trifluorobutane (see Example 3A) (3.86 g) were added to acetone (50 cm3) containing potassium carbonate (1.97 g) and the mixture stirred at ambient temperature for 7 hours. After standing for a further 16 hours, tlc showed the reaction to be incomplete, so the mixture was heated to reflux for 5 hours. The reaction was then allowed to cool, inorganic solids were filtered off and washed with more acetone. Evaporation of the combined organic layers at reduced pressure afforded a brown oil which was chromatographed on silica gel, eluting with 1:4 ethyl acetate:hexane. This gave the title pyrimidine (3.05 g). M+ =399; 1H NMR (CDCl3): δ2.2-2.4(2H,m); 3.25-3.50(2H,m); 4.68-4.95(1H,m); 4.8(2H,q); 6.73(1H,s); 8.58(1H,s); (oil).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>O1CCCC1>[CH3:25][S:26]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C1C=CC(=C(C#N)c2ccccc2)C=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
10 g (45 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile are dissolved in 100 ml of tetrahydrofuran (THF) and cooled in an ice bath. After adding 9.41 ml (68 mmol) of triethylamine to the solution, 3.83 ml (50 mmol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is gradually warmed to room temperature, and stirred for 1 hr. The reaction mixture is poured into 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 9.4 g (70%) of (4-Methylsulfonyloxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile are obtained in the form of a yellow-green crystal having a melting point of 137-139° C. (dec.). 1H-NMR shows that the product is a 82:18 mixture of the E and Z isomers (two dxd signals for H-C(2 or 6) at 6.78 and 6.91 ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccs1
Yield: 95.3 %

Procedure:
The title compound was synthesized from 4-fluoro-3-nitro-phenylamine (2.00 g, 12.81 mmol) dissolved in THF (25 ml) and Hunig's base (3.312 g, 25.62 mmol) to which was added thiophene-2-carbonyl chloride (1.878 g, 12.81 mmol) drop wise over 10 minutes. Reaction mixture was stirred at room temperature for 1 hr at which time water was added and the title compound was collected by filtration providing the title compound (3.25 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(CCN(CCN(C)C)C)C.CN(C)[CH:29]=[O:30]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:29]=[O:30]
Reactant: COc1cccc(F)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(F)c1C=O
Reaction time: 2 h
Yield: 71.8 %

Procedure:
The solution of 3-fluoroanisole (3.36 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to −78° C. and 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below −75° C. Upon the completion of the addition, N,N,N′,N′,N″-pentamethyldiethylenetriamine was added dropwise and the stirring at −78° C. was continued under an atmosphere of nitrogen for an additional two hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for half an hour. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2×150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was triturated in n-heptane. The precipitate was collected by filtration and dried to yield 2-fluoro-6-methoxybenzaldehyde (2.95 g, 0.0191 mol) as an off-white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H-].[Na+].[NH2:13]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[NH2:13][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccn1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of ethyl 1H-imidazole-2-carboxylate (2.00 g, 14.27 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (0.714 g, 17.84 mmol, 60% wt). The reaction solution was stirred at room temperature for 120 min and then was cooled to 0° C. A suspension of (aminooxy)diphenylphosphine oxide [4.66 g, 19.98 mmol, prepared from diphenylphosphinic chloride following a known procedure (Org. Lett., 351-353 (2007))], in DMF (70 ml) was added. After 10 min, the ice bath was removed. The reaction mixture became viscous and stirred at room temperature for 3 h. The reaction was quenched with water until it became a clear solution, and concentrated to dryness under reduced pressure. The crude product was suspended in EtOAc (400 ml) with stirring for 30 min and filtered. The filtrate was concentrated to give a pale yellow viscous solid, 2.6 g. The crude product was purified via silica gel column (Isco prep: 0-5% MeOH-DCM over 20 minutes) to afford ethyl 1-amino-1H-imidazole-2-carboxylate (1.99 g, 90% yield) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.35 (d, J=1.3 Hz, 1H), 7.11 (s, 1H), 4.37 (q, J=7.3 Hz, 2H), 1.50 (br. s., 9H), 1.38 (t, J=7.0 Hz, 4H). ESI-MS (analytical LCMS Method A): m/z 156.0 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[N:26]1([CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([C:3]3([C:1]#[N:2])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]3)=[CH:17][CH:18]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCNCC1
Temperature: 25 °C
Yield: 115.8 %

Procedure:
tert-Butyl 4-cyano-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-1-carboxylate (500 mg, 1.24 mmol) was stirred for 1 hour in trifluoroacetic acid (1.91 ml, 24.8 mmol) and dichloromethane (30 ml). More trifluoroacetic acid (3 ml) was added and the reaction stirred at room temperature for another hour. The reaction mixture was quenched with saturated aqueous sodium carbonate solution (15 ml) and the layers separated. The organic layer was dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1 by volume) to provide the title compound (450 mg, 18% over 2 steps). 1H NMR (400 MHz, CD3OD) δ 1.81-1.85 (m, 4H), 1.91-2.09 (m, 6H), 2.59-2.62 (m, 4H), 2.69 (t, 2H), 2.99 (t, 2H), 3.12-3.15 (m, 2H), 4.04 (t, 2H), 6.96 (d, 2H), 7.42 (d, 2H). HRMS ESI+ m/z 314.2227 [MH]+.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][CH2:13][NH:14][CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:16](N)=[O:17].Cl.[CH3:27][OH:28]>>[ClH:25].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][CH2:13][NH:14][CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:16]([O:28][CH3:27])=[O:17]
Reactant: NC(=O)C(NCCc1cccs1)c1ccccc1Cl
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C(NCCc1cccs1)c1ccccc1Cl

Procedure:
21.5 ml (0.4 mol) of 100% sulfuric acid is dissolved, under cooling in 100 ml of methanol, the solution is heated under reflux for ½ hour, then cooled to room temperature and to it 33.1 g (0.1 mol) of [2-(2-thienyl)ethylarnino](2-chlorophenyl)acetamide hydrochloride, prepared as described in Example 5., is added and the mixture is heated under reflux conditions for 10 hours. Methanol is then distilled off in vacuo and to the residue 150 ml of 1,2-dichloroethane and 150 ml of water are added, shaken well, and the two phases are separated. The aqueous layer is extracted with 2×30 ml of 1,2-dichloroethane, the combined organic layers are washed with 80 ml of 5% sodium hydroxide solution, then with 100 ml of water, dried over anhydrous sodium sulfate and evaporated in vacuo. Weight of the residue: 28.5 g. The oily product, which is the base of formula (VIII), is dissolved in 50 ml of isopropyl acetate, 7.3 ml (0.087 mol) of concentrated hydrochloric acid solution is added to it, and the mixture is stirred at room temperature for 1 hour. The precipitating product is filtered off, washed with 2×10 ml of isopropyl acetate and dried. Weight: 28.4 g (82%) mp.: 177-178° C. (lit. 175° C.).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([O:11][CH3:12])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]([O:15]C)=[O:14].O.[OH-].[Li+].O>CO>[Cl:1][C:2]1[C:10]2[C:9]([O:11][CH3:12])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccc2scc(OC)c2c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1csc2ccc(C(=O)O)c(Cl)c12
Yield: 92.2 %

Procedure:
A mixture of methyl 4-chloro-3-methoxybenzo[b]thiophene-5-carboxylate (8.35 g) and lithium hydroxide hydrate (1.37 g) was stirred in methanol (75 ml) and water (25 ml) at room temperature for 4 days. The methanol was evaporated in vacuo and the mixture poured onto excess cold dilute hydrochloric acid. The solid was filtered, washed with cold cyclohexane and dried to give 4-chloro-3-methoxybenzo[b]thiophene-5-carboxylic acid (7.28 g) as a white solid, NMR (d6DMSO) δ3.9(3H,s), 7.0(1H,s), 7.6(1H,d), 7.95(1H,d), 13.3(1H,brs).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)=[C:2]=[O:3].OC(C(F)(F)F)=O.[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:30][CH:29]([NH:31][C:32]([CH2:34][NH:35][C:36](=[O:47])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)=[O:33])[CH2:28]2)[CH2:23][CH2:22]1>CN(C=O)C>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH:1][C:2](=[O:3])[NH:20][CH:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:30][CH:29]([NH:31][C:32]([CH2:34][NH:35][C:36](=[O:47])[C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=5)=[O:33])[CH2:28]4)[CH2:25][CH2:26]3)=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(NC(=O)Nc3ccc4c(c3)OCO4)CC2)C1
Reaction time: 8 h

Procedure:
5-Isocyanato-benzo[1,3]dioxole (Aldrich, 50 mg, 0.302 mmol) was added into a solution of N-{[1-(4-amino-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide TFA salt (150 mg, 0.302 mmol) and TEA (127 μL, 0.906 mmol) in DMF (3 mL) at room temperature. The reaction was stirred overnight and quenched with saturated sodium bicarbonate. The reaction was then partitioned between DCM and water. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CN(C(OC)OC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])/[C:10](/[N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[CH:10]\[N:11]([CH3:16])[CH3:12]
Reactant: O=C(CN1CCOCC1)c1ccc(Cl)cc1Cl
Agent: COC(OC)N(C)C
Product: CN(C)/C=C(\C(=O)c1ccc(Cl)cc1Cl)N1CCOCC1

Procedure:
1 mmol of 1-(2,4-dichlorophenyl)-2-morpholin-4-ylethan-1-one was heated to 80° C. in N,N-dimethylformamidedimethyl acetal for six hours. The reaction mixture was concentrated in vacuo and purified by trituration: with diethyl ether to obtain (2E)-1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-morpholin-4-ylprop-2-en-1-one.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]3[C@@H:15]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C@@H:16]4[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:5][CH2:4]C[CH2:2]1.C1(O)CCCC1>>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]3[C:15]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:16]=4[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:2][CH2:4][CH2:5]1
Reactant: c1ccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)c(OC2CCCC2)c1
Agent: OC1CCCC1
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)c(OC2CCC2)c1

Procedure:
Following the procedure for the preparation of (5aS*,10bS*)10-[2-(cyclopentyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole and substituting cyclobutanol for cyclopentanol while making non-critical variations the title compound was obtained as 193 mg (37%) of a tan solid: mp 182.0-184.5° C. 1H NMR (400 MHz, CDCl3) δ 7.85 (br s, 1H), 7.35-7.28 (m, 3H), 7.18-7.14 (m, 1H), 7.04-7.00 (m, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 4.63-4.56 (m, 1H), 3.10-3.07 (m, 2H), 2.98-2.95 (m, 2H), 2.87-2.84 (m, 2H), 2.47-2.41 (m, 2H), 2.37-2.32 (m, 2H), 2.02-2.00 (m, 2H), 1.74-1.72 (m, 1H), 1.64-1.59 (m, 1H); HRMS (FAB) calcd for C22H24N2O+H1: 333.1967 found 333.1960.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][OH:45])=[CH:39][CH:38]=1>CCOC(C)=O>[OH:45][CH2:44][CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:38][CH:39]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCO)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 300 mg, 0.746 mmol) and THF (7.5 mL). To the resulting solution was added 2-(4-amino-phenyl)-ethanol (120 mg, 0.875 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and the resulting suspension was filtered. The solids collected were washed with 0° C. iPrOH (5 mL) and set aside. The filtrate was concentrated in vacuo and the residue obtained was dissolved in EtOAc (5 mL). The resulting solution was triturated with Hexanes (˜50 mL) to yield a precipitate. This precipitate was then filtered and washed with 0° C. iPrOH (5 mL). The solids collected were combined with those previously set aside to afford the title compound in 20% yield (0.078 g, 0.149 mmol).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[SH:22]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[S:22][C:2]1[S:3][C:4]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(Br)s1
Reactant: Sc1ccc(Cl)cc1Cl
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Yield: 25 %

Procedure:
Prepared by a similar procedure to that described as in Step D for example 22 from the 2-bromo-5-methylsulfonyl-3-nitro-thiophene (148 mg, 0.52 mmol) and 2,4-dichlorobenzenethiol (100 mg, 0.56 mmol) to afford the title product as a solid (50 mg, 25% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.35 (1H, s), 8.10 (1H, m), 8.20 (1H, m), 7.74 (1H, m), 3.42 (3H, s). MS m/z: 381.81 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([Cl:12])[C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)=[CH:2]1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH2:16][CH2:15]1>>[ClH:12].[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[CH2:18][CH2:19]2)=[CH:2]1
Reactant: ClC(c1ccsc1)c1ccsc1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: Cl
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccsc2)c2ccsc2)CC1

Procedure:
The procedure of Example 36 (a) was repeated except for using di(3-thienyl)methyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give 4-di(3-thienyl)methoxy-1-[3-(2-nitrophenoxy)propyl]piperidine hydrochloride.