Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[O:3].[CH:15](OCC)=[O:16]>>[NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][CH:15]=[O:16])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[O:3]
Reactant: CC(N)Cc1cccc(NC(N)=O)c1
Reactant: CCOC=O
Product: CC(Cc1cccc(NC(N)=O)c1)NC=O

Procedure:
A mixture consisting of 4.8 gm of 1-(3'-ureido-phenyl)-2-amino-propane and 5 ml of ethyl formate was refluxed for five hours. Thereafter, the reaction solution was evaporated, and the residue was purified by chromatography on a silicagel column, using methanol/chloroform (2:8) as the flow agent. The eluate was evaporated, and the residue was recrystallized from ethanol and ether, yielding the compound of the formula ##STR23## which had a melting point of 133°-136° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a stirring solution of benzyl 4-hydroxy-1-piperidinecarboxylate (3.55 mL, 23.4 mmol, Aldrich) and Et3N (7.18 mL, 51.5 mmol, Aldrich) in CH2Cl2 (25 mL) at room temperature was added a solution of methanesulfonyl chloride (1.99 mL, 25.8 mmol, Acros) in CH2Cl2 (25 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h and washed with 1N HCl aqueous solution, H2O and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 7.43 g of the desired product as a yellow oil. MS (ESI) 314 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:27]2[CH2:28][NH:29][CH2:30][CH2:31][CH:32]=2)=[N:24][C:25]=1[CH3:26].O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:29]1[CH2:30][CH2:31][CH:32]=[C:27]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[C:25]([CH3:26])[N:24]=2)[CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: Cc1ccc(C2=CCCNC2)nc1C
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C2=CCCN([C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)C2)nc1C
Yield: 35.7 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5,6-dimethyl-1′,2′,5′,6′-tetrahydro-2,3′-bipyridine (3.96 g, 21.0 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.35 g of the intended substance (yield 35.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:51]=[CH:50][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38]4)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]4)[C:10]=3[N:9]=2)=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)C1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OCc2nc3c(OCCCC4CCCNC4)cccc3n2CCCC2CCCNC2)cc1

Procedure:
The title compound is prepared from (S) 2-(4-chlorophenoxymethyl)-4-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole by standard deprotection techniques using trifluoroacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24](O)=[O:25].[CH:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH:33]2[CH2:34][CH2:35][N:36]([C:24]([C:11]3[CH:12]=[N:13][C:14]4[N:15]([N:16]=[CH:17][C:18]=4[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]=3[NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:25])[CH2:37][CH2:38]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: C1CCC(C2CCNCC2)CC1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)O)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(C4CCCCC4)CC3)cnc12
Yield: 99 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2,5-dimethylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (150 mg, 0.42 mmol) obtained in Example 88, step 2 and 4-cyclohexylpiperidine (U.S. Pat. No. 4,308,382, 120 mg, 0.72 mmol), the title compound (211 mg, 99%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Br:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([CH:25]=[CH:26][C:18]=3[Br:17])[C:27]#[N:28])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: N#Cc1ccc(Br)c(C(=O)O)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3Br)CC2)c(F)c1
Yield: 49 %

Procedure:
Title compound was prepared according to procedure described in example K/step2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-bromo-5-cyano-benzoic acid, (49% yield, white solid, MS (m/e): 430 (M+, 100%).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].[N:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:38]1([NH2:41])[CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:41][C:38]2([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][N:32]=3)[CH2:40][CH2:39]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2cnccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cnccn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(pyrazin-2-yl)cyclopropanamine (0.015 g, 0.011 mmol, 1.2 eq) and Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.034 g (66%). 1H NMR (400 MHz, CD3OD): δ 8.60 (d, J=1.6 Hz, 1H), 8.52 (m, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.98-7.95 (m, 2H), 7.92 (dd, J=1.6, 7.8 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.36-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.73-1.71 (m, 2H), 1.47-1.43 (m, 2H). 19F NMR (376.57 MHz, CD3OD) 6-77.68 (TFA), −112.27, −122.72 LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20](O)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27][OH:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:14]([Si:1]([O:18][CH2:19][CH:20]1[O:28][CH2:27][C:23]2=[N:24][CH:25]=[CH:26][N:22]2[CH2:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](OCC(O)Cn1ccnc1CO)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC1Cn2ccnc2CO1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Separately, prepare a −78° C. solution of 1-[tert-butyl(diphenyl)silyl]oxy-3-[2-(hydroxymethyl)imidazol-1-yl]propan-2-ol (9.4 g; 1.0 equiv; 22.89 mmoles) in dichloromethane (100 mL). Add the in situ prepared iodinating reagent dropwise to this solution with the orange color quickly fading to nearly colorless. Maintain the solution at −78° C. for 30 minutes, then allow it to warm to 0° C. and maintain for 10 minutes. Recool the solution to −78° C., and add tetrahydrofuran (150 mL) followed by 60% sodium hydride (2.20 g; 2.4 equiv; 54.95 mmoles). Slowly warm the solution to 0° C. over 30 minutes, and then to ambient temperature for 1 hour. Pour the mixture slowly into 50% saturated sodium bicarbonate solution and extract with dichloromethane (4×100 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate. Purify the crude product by column chromatography (10 to 100% ethyl acetate in hexanes) to afford the desired product contaminated with triphenylphosphine oxide. Further purify by SCX ion-exchange chromatography (10% methanol in dichloromethane to 10% (4N ammonia in methanol) in dichloromethane) to afford the desired tert-butyl-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-ylmethoxy)-diphenyl-silane (5.96 g; 66%) as a colorless gum. MS (m/z): 393(M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[OH-].[K+].[CH:17](=O)[CH2:18][CH2:19][CH3:20]>CCO.[Pd]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCC2=O
Reactant: CCCC=O
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC1Cc2cc(NC(C)=O)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
5-(Acetylamino)-1-indanone (10.0 g, 52.3 mmol) was added to a solution of KOH (87.7%, 0.66 g, 10.3 mmol) in EtOH (200 mL). The resulting suspension was stirred at room temperature while butyraldehyde (6.1 mL, 67.8 mmol) was added dropwise over two minutes. After stirring at room temperature for an additional 15 minutes, the mixture was treated with 10% Pd/C and stirred under a H2 atmosphere (balloon) for 19 hours. The mixture was filtered through a pad of silica gel and the pad washed with EtOAc. The filtrate was washed with 1N HCl, 5% NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated under vacuum to an orange oil (12 g). The crude product was purified by Biotage flash chromatography on a 75 L silica gel column (7.5×35 cm), eluting with 2:1 hexane-EtOAc, to afford 5-(acetylamino)-2-butyl-1-indanone (8.8 g, 69%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([F:19])[CH:17]=[C:16]([F:20])[CH:15]=3)[NH:1][C:22]2=[O:24])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1cc(F)cc(F)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(F)cc(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3,5-difluorobenzamide (760 mg, 2.23 mmol) in THF (10 mL) was treated portionwise with triphosgene (722 mg, 2.43 mmol). The solution was stirred at room temperature for 60 min, then was treated dropwise with saturated aqueous NaHCO3 and stirred until no more gas evolution was observed. The organic phase was separated, washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-100%), to give 3-(3-bromo-2-methylphenyl)-6,8-difluoroquinazoline-2,4(1H,3H)-dione (820 mg), used without further purification. Mass spectrum m/z 367, 369 (M+H)+, 389, 391 (M+Na)+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:16][C:15]3[C:10](=[N:11][C:12](S(C)(=O)=O)=[N:13][CH:14]=3)[N:9]([CH3:21])[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:25]([CH2:36][CH3:37])[CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:24]>>[CH:1]1([N:7]2[CH2:16][C:15]3[C:10](=[N:11][C:12]([NH:33][C:32]4[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:25]([CH2:36][CH3:37])[CH2:23][CH3:24])=[CH:35][CH:34]=4)=[N:13][CH:14]=3)[N:9]([CH3:21])[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)N(C2CCCCC2)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(C2CCCCC2)C3)cc1
Temperature: 180 °C
Yield: 17.8 %

Procedure:
A mixture of 100 mg (0.31 mmol) of 3-cyclohexyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2-(1H)-one and 400 mg (1.9 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 40 ml of dichloromethane. The solution was washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered off and dried to give 25 mg (18%) 3-cyclohexyl-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 90-92° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][CH3:11])[CH2:8][CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=O.[NH3:19]>CO>[C:15]([O:14][C:12]([N:6]1[CH2:7][CH2:8][C@H:9]([O:10][CH3:11])[C@H:5]1[C:3](=[O:2])[NH2:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: N
Reactant: COC(=O)[C@@H]1[C@@H](OC)CCN1C(=O)OC(C)(C)C
Solvent: CO
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(N)=O
Yield: 31 %

Procedure:
(2S,3S)-3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (518 mg, 2.0 mmol) was stirred in 7M ammonia in methanol (5 mL) for 4 days. The reaction mixture was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, gradient 0 to 6% methanol in DCM) to give (2S,3S)-2-Carbamoyl-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (153 mg, 31%). 1H NMR 400 MHz (DMSO-d6) δ: 7.54 (1 H, br, s), 7.09 (1 H, br, s), 4.09-4.00 (1 H, m), 3.78 (1 H, m), 3.47 (1 H, m), 3.26 (3 H, s), 1.93 (3H, m), 1.37 (9 H, s)
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:41])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=4)[N:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[S:15][CH:16]=1.S(OC)(O[CH3:46])(=O)=O>C1COCC1.CN(C=O)C>[CH3:46][N:17]([C:14]1[S:15][CH:16]=[C:12]([CH3:11])[N:13]=1)[C:18](=[O:41])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)Nc4nc(C)cs4)cc3)c2cc1OC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(CC(=O)N(C)c4nc(C)cs4)cc3)c2cc1OC
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon, a 1M solution of lithium hexamethyldisilazane in THF (0.52 ml) was added dropwise to a stirred solution of N-(4-methylthiazol-2-yl)-2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetamide (0.205 g) in DMF (4 ml) that had been cooled to −5° C. After 5 minutes, a solution of dimethyl sulphate (0.049 ml) in DMF (1 ml) was added dropwise and the resultant mixture was stirred at 0° C. for 30 minutes. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.105 g); 1H NMR: (DMSOd6) 2.29 (d, 3H), 3.73 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 4.17 (s, 2H), 6.5 (d, 1H), 6.82 (s, 1H), 7.52 (d, 2H), 7.4 (s, 1H), 7.42 (d, 2H), 7.5 (s, 1H), 8.49 (d, 1H); Mass Spectrum: M+H+ 450.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][CH2:2][C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1)=[O:15]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: NCc1cc(N)nc(N)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Nc1cc(CNC(=O)c2ccccc2Br)cc(N)n1
Yield: 20.2 %

Procedure:
A solution of 172.5 mg (1.25 mmol) 4-aminomethyl-pyridine-2,6-diamine in 5 ml pyridine was treated with 275 mg (1.25 mmol) o-bromobenzoylchloride and a catalytic amount 4-dimethylaminopyridine and stirred for 2.5 h at room temperature. The mixture was evaporated to dryness and the residue was purified by column chromatography on silica eluting with dichloromethane/methanol 9/1 to yield 81 mg (20%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:12]([OH:14])[CH3:13].Cl>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7](=[NH:8])[O:14][CH2:12][CH3:13]
Reactant: COc1ccc(Cl)cc1C#N
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)c1cc(Cl)ccc1OC
Reaction time: 120 h
Yield: 101.4 %

Procedure:
A cooled solution of 5-chloro-2-methoxybenzonitrile (9.3 g, 0.056 mol, Maybridge) and ethanol (16.2 mL, 0.28 mol) in CH2Cl2 (40 mL) was bubbled with HCl gas at 0° C. for 30 min. The reaction mixture was kept in refrigerator for 5 days. The reaction mixture was then concentrated and triturated with diethyl ether to remove unreacted starting material. The precipitate was dried under reduced pressure to obtain 7.1 g (51%) of the title compound. MS (ESI+) m/z 214 (M+H)+.
Reaction SMILES: [N+]([C:4]1C=CC=CC=1O)([O-])=O.[Br:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[Br:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[O:21][CH3:4]
Reactant: O=[N+]([O-])c1cccc(O)c1Br
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
The nitrophenol starting material B2 (3.1 g; 14.2 mmol) was dissolved in DMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1 mmol) followed by MeI (2.6 mL; 42.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated, the residue taken up in ether (1×200 mL), washed with water (1×200 mL), brine (4×100 mL), dried (MgSO4), filtered and evaporated to afford the crude 2-bromo-3-nitroanisole B3 (94%; 3.1 g) as an orange solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:8](=[O:12])[N:9]([CH3:11])[NH2:10])([CH3:7])[OH:6])C.[NH3:14]>>[NH2:10][N:9]([C:8]([C:5]([CH3:7])([OH:6])[C:4]([NH2:14])=[O:3])=[O:12])[CH3:11]
Reactant: CCOC(=O)C(C)(O)C(=O)N(C)N
Reactant: N
Product: CN(N)C(=O)C(C)(O)C(N)=O

Procedure:
2-Azaalanyl-dl-lactic acid ethyl ester (0.02 mole) is treated with liquid ammonia (50 ml) at room temperature for 16 hours. The mixture is evaporated to dryness. Chromatography on silica gel (80 gm) and elution with 15% methanol in chloroform gives 2-azaalanyl-dl-lactamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:19]=1.C1C(=O)N([Br:27])C(=O)C1>C1COCC1>[Br:27][C:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][C:7]=2[S:8][C:9]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a 500 mL round bottom flask containing 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (22 g, 81 mmol) in THF (250 mL) at 0° C. was added NBS (15 g, 84 mmol). The reaction mixture was stirred at 0° C. for 60 min and then allowed to warm to room temperature and stirred for an additional 2 h. Upon completion the reaction mixture was concentrated to 50% volume and quenched with sat. aq. sodium thiosulfate solution. The resulting solution was extracted with diethyether 3× and the combined organic solvent was dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 3-bromo-6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene (27.5 g, 79 mmol, 97% yield). 1H NMR (400 MHz, CDCl3) δ ppm=7.63 (d, J=9.1 Hz, 1 H), 7.55-7.61 (m, 2 H), 7.19 (d, J=2.5 Hz, 1 H), 6.96-7.02 (m, 1 H), 6.87-6.95 (m, 2 H), 3.81 (s, 3 H), 3.79 (s, 3 H).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[C:8]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[OH:20].CI>CCCCCC>[CH3:3][O:20][CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CN(C)C=O
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Product: CCCCCCC(CC=CCCCCCCCC(=O)OCC)OC
Temperature: 40 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a 1-l flask equipped with a stirrer, a dropping funnel and a condenser, 24 g (0.6 mol) of 60% sodium hydride, 500 ml of dimethylformamide were charged, followed by the dropwise addition of a solution of 163.3 g (0.5 mol) of ethyl ricinoleate in 142 g (1.0 mol) of methyl iodide over one hour while stirring at 40° C. under an N2 atmosphere. After the completion of the dropwise addition, stirring was conducted at 40° for further 6 hours. To the reaction mixture so obtained, hexane was added. The resulting mixture was then washed with an aqueous solution of ammonium chloride and an aqueous solution of sodium thiosulfate, followed by concentration under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 155.8 g of ethyl 12-methoxy-9-octadecenoate were obtained (yield: 92%).