Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=3)[C:20]([OH:30])=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH:22]=2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47].CCOC(C)=O>CN(C=O)C.O>[C:49]([O:48][C:46](=[O:47])[CH2:45][O:30][C:20]1[C:19]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:18][C:17]([C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22][C:21]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of 2′-hydroxy-3,3″-dimethyl-[1,1′:3′,1″]terphenyl-5′-carboxylic acid (7-phenyl-heptyl)-amide (240 mg, 0.516 mmol) in 2.5 mL anhydrous DMF was added solid K2CO3 (84 mg, 0.613 mmol). The reaction mixture was stirred at room temperature for 2 min before t-butyl bromoacetate (158 mg, 0.812 mmol, 812 μL) was added. The reaction was stirred overnight at room temperature after which point it was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with water to remove DMF. Then they were dried with Na2SO4 and the solvent was removed in vacuo to give an oil that was subjected to flash column chromatography (15% EtOAc: 85% Hexanes) to yield 180 mg, 60% of a colorless oil. 1H NMR (CDCl3) δ 1.25 (s, 9H); 1.25–1.40 (m, 6H); 1.28–1.47 (m, 4H); 2.40 (s, 6H); 2.57 (t, J=8.18 Hz, 2H); 3.43 (quartet, J=8.18 Hz, 2H); 3.73 (s, 2H); 6.06 (t, J=5.73 Hz, 1H); 7.08–7.20 (m, 5H); 7.20–7.32 (m, 4H); 7.37–7.46 (m, 4H); 7.68 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8]O)[CH2:4][CH2:3]1.[H-].[Na+].F[C:13]1[C:14]([O:26][CH3:27])=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[CH:18]=1.C1C[O:31]CC1>>[CH3:27][O:26][C:14]1[C:13]([O:31][CH2:1][N:2]2[CH2:3][CH2:4][CH:5]([CH3:8])[CH2:6][CH2:7]2)=[CH:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1
Reactant: C1CCOC1
Reactant: CN1CCC(CO)CC1
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1F
Agent: [H-]
Agent: [Na+]
Product: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1OCN1CCC(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-4-piperidinemethanol (0.566 g, 4.3 mmol) in THF (25 ml) at 0° C. was added, portion wise, 60% NaH (0.63 g, 15.48 mmol) and the mixture stirred for 15 mins. N-(5-Fluoro-4-methoxy-2-nitro-phenyl)-acetamide [U.S. Pat. No. 4,431,807] (1 g, 4.38 mmol) in THF (40 ml) was added to reaction, which was stirred at RT for 30 mins followed by heating at 50° C. for 1 hour. The reaction was quenched with water and then extracted with EtOAc twice, the organic portion was washed with brine, dried over MgSO4, filtered and reduced in vacuo to yield N-[4-methoxy-5-(4-methyl-piperidin-1-ylmethoxy)-2-nitro-phenyl]-acetamide (1.34 g), (LC/MS (acidic method): Rt 1.84, [M+H]+ 338)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[C:20](#[N:23])[CH:21]=[CH2:22]>>[C:20]([CH2:21][CH2:22][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)#[N:23]
Reactant: C=CC#N
Reactant: c1ccc(N2CCOCC2)c(N=C2CCCCN2)c1
Product: N#CCCN1CCCCC1=Nc1ccccc1N1CCOCC1

Procedure:
The product of Example 1 (2.6 g) was reacted at room temperature with excess acrylonitrile (5 ml). The product was recrystallised from ethylacetate to give 4((2-[1-(2-cyanoethyl)-2-piperidinylideneamino]phenyl))morpholine. (m.p. 148° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=O)=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].Cl.[NH2:24][OH:25].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[N:24][OH:25])=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(CC=O)ccc1OCCNc1ncnc(C)c1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(CC=NO)ccc1OCCNc1ncnc(C)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
6.0 g of 5-chloro-4-[2-(4-formylmethyl-2-methylphenoxy)ethylamino]-6-methylpyrimidine were dissolved in 50 ml of ethanol, and a solution of 1.4 g of hydroxylamine hydrochloride in 5 ml of water was added thereto. Subsequently, a solution of 0.8 g of sodium hydroxide in 5 ml of water was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. It was then poured into water. Crystals precipitated, and these were collected by filtration, washed with water and dried to obtain 5.2 g of 5-chloro-4-{2-[4-(2-hydroxyiminoethyl)-2-methylphenoxy]ethylamino}-6-methylpyrimidine as an intermediate.
Reaction SMILES: COC1C=C(C=CC=1OC)C[NH:7][C:8]1[N:30]=[CH:29][C:11]2[C:12]3[N:13]([CH:17]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[C:22]([CH3:28])[N:21]=4)[N:19]=3)[CH2:14][CH2:15][O:16][C:10]=2[CH:9]=1>C(O)(C(F)(F)F)=O>[CH:25]([N:24]1[C:20]([C:18]2[N:19]=[C:12]3[C:11]4[CH:29]=[N:30][C:8]([NH2:7])=[CH:9][C:10]=4[O:16][CH2:15][CH2:14][N:13]3[CH:17]=2)=[N:21][C:22]([CH3:28])=[N:23]1)([CH3:27])[CH3:26]
Reactant: COc1ccc(CNc2cc3c(cn2)-c2nc(-c4nc(C)nn4C(C)C)cn2CCO3)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N)cc2OCC3)n(C(C)C)n1
Temperature: 65 °C
Yield: 30.7 %

Procedure:
N-(3,4-dimethoxybenzyl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine (190 mg, 0.40 mmol) was dissolved in TFA (3.0 mL) and heated at 65° C. for 30 min. The reaction mixture was cooled to ambient temperature and concentrated to dryness in vacuo. The crude residue was purified via HPLC to afford 463 as a white solid (40 mg, 31%). LC/MS (ESI+): m/z 326 (M+H). 1H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 7.76 (s, 1H), 6.19 (s, 2H), 5.98 (s, 1H), 5.88-5.76 (m, 1H), 4.45 (dd, J=14.4, 5.6 Hz, 4H), 2.24 (s, 3H), 1.44 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([CH:21]=[C:22]([CH:24]=O)[N:23]=3)[CH:20]=2)=[N:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2].[CH3:26][NH:27][CH3:28].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH3:26][N:27]([CH2:24][C:22]1[N:23]=[C:18]2[CH:17]=[CH:16][C:15]([C:4]3[C:3]([CH2:1][CH3:2])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:13][CH3:14])[N:5]=3)=[CH:20][N:19]2[CH:21]=1)[CH3:28]
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2nc(C=O)cn2c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2nc(CN(C)C)cn2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
To a solution of methyl 5-ethyl-6-(2-formylimidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinate (90 mg, 0.27 mmol) in dichloroethane (1.5 mL) was added solution of dimethylamine (2M THF, 0.20 mL, 0.40 mmol) followed by AcOH (25 μL, 0.42 mmol). After stirring at room temperature for 5 min NaBH(OAc)3 (90 mg, 0.42 mmol) was added. Reaction was stirred at room temperature ˜1.5 h and monitored by LC/MS until starting aldehyde was completely consumed. Reaction was diluted with DCM (5 mL) and then quenched with NaHCO3 (aqueous saturated, 5 mL). Product was extracted with DCM (3×5 mL). Organic phase was washed with NaCl (aqueous saturated, 10 mL) and dried over Na2SO4. Removal of the solvent afforded methyl 6-(2-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-ethyl-2-methoxynicotinate (100.6 mg) which was used directly in the next step. LC-MS 369.3 [M+H]+, RT 0.83 min.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=O>CO.Cl.O>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:13][CH:14]=1
Reactant: O=C(CCCCl)c1ccc(O)cc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCCCl)c1ccc(O)cc1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
Thiosemicarbazide (6.84 g, 75 mmol) was added under nitrogen to a solution of 4-chloro-4'-hydroxybutyrophenone (10.0 g, 50 mmol) in 175 mL of methanol plus 13.5 mL of 1 N HCl plus 12.5 mL of water and the reaction stirred room temperature for forty hours. The reaction was concentrated under reduced pressure to remove most of the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 8.33 g of a white solid. Recrystallization of the solid from isopropyl alcohol gave 3.19 g (21%) of the title compound as a light yellow solid, mp 126-129° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[N:23]=[CH:24][N:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)[C:21]=2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH:56]2[CH2:58][CH2:57]2)[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[C:21]4[CH:20]=[CH:19][N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH:56]3[CH2:58][CH2:57]3)[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: O=C(N[C@@H](C1CC1)C(F)(F)F)c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)N[C@@H](C6CC6)C(F)(F)F)cn5)C4)c3)ncnc21
Temperature: 125 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (110 mg, 0.22 mmol) and 5-chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamide (58 mg, 0.21 mmol) in NMP (2.0 mL). The reaction mixture was stirred at 125° C. for 2 h. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-65%) to afford the desired product (80 mg, 59%). LCMS (M+H)+: m/z=653.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:19])[C:16]([CH3:18])([CH3:17])[C@H:9]1[CH2:10][C:11]1C(OS(C(F)(F)F)(=O)=O)=[CH:22][CH:21]=[CH:20][C:12]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH3:33].C(O[CH2:38][CH3:39])(=O)C>CN(C)C=O.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.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:19])[C:16]([CH3:18])([CH3:17])[C@H:9]1[CH2:10][C:11]1[C:39]([C:38]#[N:33])=[CH:22][CH:21]=[CH:20][C:12]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CC1(C)[C@H]2Cc3c(OS(=O)(=O)C(F)(F)F)cccc3[C@]1(C)CCN2Cc1ccccc1
Reactant: N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2Cc3c(C#N)cccc3[C@]1(C)CCN2Cc1ccccc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2.79 g) is added to a mixture of (2R,6S)-trifluoro-methanesulfonic acid 3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-yl ester (7.30 g) and zinc cyanide (2.85 g) in dimethylformamide (35 mL) kept in argon atmosphere. The resulting mixture is stirred at 100° C. for 6 h. After cooling to room temperature, water (300 mL), concentrated ammonia solution (10 mL), and ethyl acetate (150 mL) are added and the forming precipitate is separated by filtration. The organic layer of the filtrate is separated and the aqueous layer is extracted twice with ethyl acetate. The combined organic phases are washed with brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 19:1) to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[ClH:14].[C:15]1(C)[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1>C(OCC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:14])=[CH:17][CH:16]=1)=[CH:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(Cl)c(Cl)cc21
Reactant: Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Clc1ccc(C2=CCCc3cc(Cl)c(Cl)cc32)cc1

Procedure:
Magnesium turnings (1.5 g.) and diethyl ether (30 ml.) were stirred while a solution of p-bromochlorobenzene (12 g.) in diethyl ether (100 ml.) was added to form the Grignard reagent. The solution was heated under reflux for 10 minutes, then a solution of 6,7-dichloro-1,2,3,4-tetrahydro-1-oxonaphthalene (9 g.) in diethyl ether (100 ml.) was added over 20 minutes, and the mixture was then heated under reflux for 30 minutes. The reaction mixture was cooled and acidified with 2N hydrochloric acid (50 ml.), and the ether layer was separated, dried, and evaporated to dryness leaving an oil. This residual oil was dissolved in toluene (300 ml.), toluene-p-sulphonic acid (0.5 g.) was added, and the solution was heated under reflux in an Dean and Stark apparatus for 2 hours, while 0.5 ml. of water was collected. The toluene was evaporated under reduced pressure and the residual oil was chromatographed on silica (Merck's Grade 7734) using petroleum ether (b.p. 60°-80° C.) as the eluant, to give 6,7-dichloro-1-(4-chlorophenyl)-3,4-dihydronaphthalene as a white crystalline solid, m.p. 106°-108° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([O:23]C)(=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:25][NH:26][CH2:27][CH2:28][OH:29]>>[C:1]([O:29][CH2:28][CH2:27][N:26]([C:4](=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:25])(=[O:2])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Reactant: C[O-]
Reactant: CNCCO
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCC(=O)OCCN(C)C(=O)CCCCCCCCCCCCCCCCC

Procedure:
50 Parts by weight of 28% sodium methylate is added to 100 parts by weight of methyl stearate and 26 parts by weight of N-methylethanolamine, and an amidation reaction is allowed to proceed at 90° C. while removing methanol. Subsequently, sodium methylate is decomposed by using 66 parts by weight of 35% hydrochloric acid and after dehydration, sodium chloride is removed by filtration. Thereafter, 33 parts by weight of stearic acid is added to 100 parts by weight of the solid material, and an esterification reaction is performed at 170° C. while effecting dehydration, whereby N-stearoyl-N-methylamino-ethyl stearate is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([OH:11])[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].[CH3:22][C:23]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH3:24].N1C=CN=C1>CN(C=O)C.C(Cl)Cl>[Si:26]([O:11][C@@H:8]1[CH2:9][CH2:10][C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[C@H:6]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:7]1)([C:23]([CH3:25])([CH3:24])[CH3:22])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of compound 34d (10.9 mmol) in DMF (35 mL) were added TBDPSCl (24.0 mmol) and imidazole (32.7 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was then diluted with DCM (140 mL) and washed sequentially with 1N HCl (140 mL) and H2O (140 mL). Organics were dried, concentrated, and purified by silica gel chromatography (PE/EtOAc) to yield compound 35 as a colourless oil in 65% yield.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([NH:6][CH2:7][CH:8]1[O:22][C:11]2=[C:12]3[C:17](=[C:18]([CH3:20])[CH:19]=[C:10]2[CH2:9]1)[NH:16][C:15](=[O:21])[CH:14]=[CH:13]3)=[O:5])[CH3:3].[H][H]>O.[Pd]>[NH2:1][C@@H:2]([C:4]([NH:6][CH2:7][CH:8]1[O:22][C:11]2=[C:12]3[C:17](=[C:18]([CH3:20])[CH:19]=[C:10]2[CH2:9]1)[NH:16][C:15](=[O:21])[CH2:14][CH2:13]3)=[O:5])[CH3:3]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@@H](C)N)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNC(=O)[C@@H](C)N)C2
Yield: 49.4 %

Procedure:
The compound obtained in Example 228 (680 mg, 2.0 mmol) was dissolved in water (30 ml). To the obtained solution, 10% palladium-on-carbon (600 mg) was added, followed by stirring at 80° C. for 10 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was purified by silica gel column chromatography (chloroform: methanol =5:1). The obtained crystals were dissolved in methanol (5 ml), and 4N-HCl dioxane (1 ml) was added thereto while cooling on ice. The mixture was condensed under reduced pressure. The resultant residue was recrystallized from methanol--ether, to obtain 300 mg of the title compound as colorless powdery crystals (44.1%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[CH:27]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][N:26]1[CH:30]=[C:29]([S:31]([N:22]2[CH2:23][CH2:24][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:20][CH2:21]2)(=[O:33])=[O:32])[N:28]=[CH:27]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cnc(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (40 mg, 0.12 mmol) in methylene chloride (5 mL) at 0° C., 1-methyl-1H-imidazole-4-sulfonyl chloride (27.1 mg, 0.14 mmol) and triethylamine (0.07 mL, 0.50 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min. Then the reaction mixture was partitioned between methylene chloride and water, the aqueous layer was extracted with methylene chloride (25 mL×2) and combined organic phase was dried with Mg2SO4 and concentrated by reduce pressure, and purified by Gilson HPLC (reverse phase, eluting with CH3CN/Water, 0.1% TFA, 10/90, v/v, over 15 min) to give the title compound (22.5 mg, 39%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH:10](C#N)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](=[O:16])=[O:15]>[OH-].[Ba+2].[OH-]>[CH2:1]([N:8]1[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=O
Reactant: N#CC1CN(Cc2ccccc2)C1
Agent: [Ba+2]
Agent: [OH-]
Product: O=C(O)C1CN(Cc2ccccc2)C1

Procedure:
1.5 g of 13B in 10 ml of saturated barium hydroxide solution was heated under reflux for 30 hours. The reaction mixture was cooled, saturated with gaseous carbon dioxide and filtered. The solvent was removed from the filtrate under reduced pressure to give 1-benzylazetidine-3-carboxylic acid (13C).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH2:11]([CH:13]([CH2:18][CH2:19][OH:20])[CH:14](C)[CH2:15][OH:16])[CH3:12].C([N:23](CC)CC)C.CCOC(C)=O.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:23][CH:14]([CH2:15][OH:16])[CH:13]([CH2:11][CH3:12])[CH2:18][CH2:19][OH:20])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCN(CC)CC
Reactant: CCC(CCO)C(C)CO
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(CCO)C(CO)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 7.1 %

Procedure:
5-Chlorothiophene-2-sulfonyl chloride (6.4 g, 24.48 mmol) was added dropwise (5 min) as a solution in CH2Cl2 (5 mL) to a 0° C. solution of 3-ethyl-2-methylpentane-1,5-diol (2.85 g, 19.34 mmol) in CH2Cl2 (30 mL) and triethylamine (5.66 mL, 40.81 mmol). The solution was allowed to warm to 25° C. overnight (19 h). An aliquot was taken and TLC (1:1 EtOAc-hexane) indicated that reaction was complete. It was diluted with CH2Cl2 (50 mL) and the organic layer was washed with 1N HCl (2×50 mL) and saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude oil (4.9 g). The crude product was purified by column chromatography, silica gel 230-400 mesh, eluant: 1:4 EtOAc-hexane to afford 5-chloro-N-[2-ethyl-4-hydroxy-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as an amorphous white solid (0.450 g, 7.3%). Mass Spectrum (−ESI): 326 (M−H)−.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][O:37][CH3:38]>>[ClH:20].[CH3:30][O:31][CH2:32][CH2:33][N:34]([CH2:35][CH2:36][O:37][CH3:38])[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:21]1[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: COCCNCCOC
Product: COCCN(CCOC)CCOc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1
Product: Cl

Procedure:
6-(2-[bis-(2-methoxy-ethyl)-amino]-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 40% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and bis-(2-methoxy-ethyl)-amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(O)C.O=[Pt]=O>[C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=NNC(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCNNC(=O)OC(C)(C)C
Yield: 97.5 %

Procedure:
A slurry of N′-ethylidene-hydrazinecarboxylic acid tert-butyl ester (5.0 g, 32 mmol), acetic acid (48 μL) and PtO2 (250 mg) in ethanol (50 mL) was shaken under a 40 psi pressure of H2 in a Parr hydrogenator for 24 h. The mixture was filtered through Celite to provide N′-ethylhydrazinecarboxylic acid tert-butyl ester (5 g) as a clear oil. MS (ESI+) for C7H16N2O2 m/z 161.0 (M+H)+.