Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[OH-].[Ca+2:8].[OH-].[O-2].[Ca+2]>>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Ca+2:8].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Agent: [Ca+2]
Agent: [O-2]
Agent: [OH-]
Product: CC(O)C(=O)[O-]

Procedure:
Food grade (80%) lactic acid in the amount of 14.4 kg is divided into three equal fractions. Calcium hydroxide, 4.2 kg, and 0.39 kg of calcium oxide are combined, mixed, and divided into three equal fractions. The first fraction of lactic acid is added to 9.8 kg of almond shell meal while stirring. Then, the first fraction of the combined base mixture is slowly added while stirring. The temperature of the mixture is observed to increase and water starts evaporating. When the product appeared to be dry, the same procedure was repeated for the remaining fractions, adding the acid while stirring, adding the base while stirring and drying.
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)(=[O:5])=[O:4].I[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][CH2:2][S:3]([N:6]([CH2:18][CH3:19])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)(=[O:4])=[O:5]
Reactant: O=[N+]([O-])c1cc(NS(=O)(=O)CCl)ccc1F
Reactant: CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ccc(F)c([N+](=O)[O-])c1)S(=O)(=O)CCl
Yield: 71.4 %

Procedure:
A solution of 1-chloro-N-(4-fluoro-3-nitrophenyl)methanesulfonamide (5.93 g, 22.1 mmol), iodoethane (3.79 g, 24.3 mmol), tetrabutylammonium bromide (0.712 g, 2.21 mmol), and anhydrous K2CO3 (8.85 g, 64 mmol) in anhydrous dimethylformamide (40 mL) was stirred at room temperature. When the starting material had disappeared based on thin layer chromatography on silica (6 h), the reaction mixture was poured into water (200 mL) and extracted with CH2Cl2 (500 mL). The organic extract was washed with water (two times with 50 mL), dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, 1-chlorobutane and diethyl ether 100:1 v/v eluent) to give 4.68 g of the title compound of Step B as a solid melting at 80°-83° C. 1H NMR (Me2SO-d6, 400 MHz): δ8.17 (dd,1H, J=6.75 and 2.7Hz), 7.85 (dd,1H, J=9.4 and 3 Hz), 7.69 (dd,1H, J=11 and 9 Hz), 5.25 (s,2H), 3.83 (q,2H), 1.04 (t,3H).
Reaction SMILES: N[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: COc1cccc(C(=O)O)c1N
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(C(=O)O)c1Br
Temperature: 60 °C
Yield: 74 %

Procedure:
To 2-amino-3-(methyloxy)benzoic acid (4.00 g, 23.9 mmol) in 10% aqueous hydrobromic acid (54 ml) at 0° C. was added sodium nitrite (1.65 g, 23.9 mmol) in water (17 ml). To this solution was added dropwise a solution of copper (I) bromide (3.78 g, 26.3 mmol) in 48% hydrobromic acid (22 ml) and heated to 60° C. for 2 h. The mixture was cooled to 0° C., and the resultant precipitate was collected by filtration, washed with cold water and recrystallized from water to give pure 2-bromo-3-(methyloxy)benzoic acid (4.07 g, 74%). MS (EI) for C8H7BrO3: 232 (MH+).
Reaction SMILES: Cl[TeH:2]1(Cl)(Cl)[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=2[NH+:5]=[C:4]([CH3:14])[O:3]1.NN>C(O)C>[C:4]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[Te:2][Te:2][C:7]1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=1[NH:5][C:4](=[O:3])[CH3:14])(=[O:3])[CH3:14]
Reactant: COc1ccc2c(c1)[NH+]=C(C)O[TeH]2(Cl)(Cl)Cl
Agent: NN
Solvent: CCO
Product: COc1ccc([Te][Te]c2ccc(OC)cc2NC(C)=O)c(NC(C)=O)c1
Temperature: 25 °C

Procedure:
1,1,1-Trichloro-6-methoxy-3-methyl-2,1,4-benzoxatellurazinium, inner salt (Example 11) (5.0 g=0.0125 mole) was dissolved in 50% aqueous ethanol (200 ml). The solution heated to boil, and hydrazine (1 ml) was added with stirring. The deep orange solution was cooled slowly to room temperature to deposit fibrous needles which, upon filtration and drying, yielded a tan solid (3.25 g, 89% of theory), m.p. 181°-182° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C@H:8]([OH:24])[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:24])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc([C@H](O)CC(c2ccccc2)c2ccccc2C)ccn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C[C@H](c2ccccc2)c2ccccc2C)ccn1
Temperature: 90 °C
Yield: 0.1 %

Procedure:
A mixture of (R)-1-(2-methylpyridin-4-yl)-3-phenyl-3-o-tolylpropan-1-ol (110 mg, 347 mmol), and manganese dioxide (121 mg, 1.39 mmol) in toluene (2 mL) was heated at 90° C. for 3 h, then filtered through diatomaceous earth and concentrated in vacuo. Chromatography (silica gel, 10 g, 10% to 50% ethyl acetate in heptane) produced the title compound (60 mg, 55%). White semisolid, MS (ESI+): m/z=316.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([N+]([O-])=O)[C:6]=1[CH:17]=[CH:18][N:19](C)C)[CH3:2].Cl[Sn]Cl>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[CH:17]=[CH:18][NH:19][C:7]=2[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:22])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C=CN(C)C
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc2[nH]ccc12
Yield: 39.7 %

Procedure:
A mixture of 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid ethyl ester (11.3 g, 0.037 mol) and SnCl2 (83 g. 0.37 mol) in ethanol was heated at reflux for 4 h. The mixture was concentrated to dryness and the residue was poured into water and basified with sat. Na2CO3 solution to pH 8. The precipitate was filtered off and the filtrate was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (2×100 mL) and brine (150 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-1H-indole-4-carboxylic acid ethyl ester (B-18) (3 g, 40%). 1H NMR (DMSO-d6) δ 10.76 (br s, 1 H), 7.11-7.14 (m, 2 H), 6.81-6.82 (m, 1 H), 6.67-6.68 (m, 1 H), 4.94 (br s, 2 H), 4.32-4.25 (q,J=7.2 Hz, 2 H), 1.35-1.31 (t,J=7.2, 3 H). ESI-MS 205.0 m/z (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].CO>C(O)(=O)C>[CH3:1][N:2]([CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:5])[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CNCC(C)c1ccncc1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N(C)CC(C)c1ccncc1
Reaction time: 8 h

Procedure:
dl-4-(1-Methylaminoprop-2-yl)pyridine (4.5 g.) in acetic acid (15 ml.) was treated cautiously with acetic anhydride (10 ml.) followed by allowing the mixture to stand at ambient temperature overnight. Methanol (20 ml.) was then added to destroy excess acetic anhydride, followed by evaporation in vacuo (at 40° C.) to remove methanol and methyl acetate. The residue was diluted with water and treated portionwise with sodium carbonate (anhydrous) until alkaline (pH 10-12). The oily suspension was extracted with chloroform (3×60 ml.) and the bulked extracts were dried (Na2CO3) and evaporated to dryness in vacuo to give a near-colorless oil (6.8 g.). The oil was distilled to give pure dl-4-(1-[N-methylacetamido]prop-2-yl)pyridine (3 g.), b.p. 138°-140°/0.4 mm Hg. (as a colorless oil).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:33][N:32]([CH3:34])[C:30]([C:29]1[CH:35]=[CH:36][C:26]([NH:25][C:2]2[CH:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH:14]=3)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:27][CH:28]=1)=[O:31]
Reactant: CN(C)C(=O)c1ccc(N)cc1
Reactant: NC(=O)c1cnc(Cl)cc1NCc1cccc(-c2ccccn2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(Nc2cc(NCc3cccc(-c4ccccn4)c3)c(C(N)=O)cn2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a mixture of 6-chloro-4-(3-(pyridine-2-yl)benzylamino)nicotinamide (82 mg, 0.24 mmol) in p-Dioxane (2.5 mL) was added 4-amino-N,N-dimethylbenzamide (51 mg, 0.31 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), BINAP (30 mg, 0.05 mmol) and Cs2CO3 (234 mg, 0.72 mmol). After stirred at 80° C. for 15 h, it was concentrated and purified by preparative HPLC to give 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(pyridine-2-yl)benzylamino)nicotinamide. MS found for C27H26N6O2 as (M+H)+ 467.4. UV: λ=259.2, 301.6 nm. 1H NMR: (CD3OD) δ 8.75 (dd, J=11.2, 5.2 Hz, 1H), 8.34 (m, 1H), 8.23 (d, J=5.6 Hz, 1H), 8.14 (m, 1H), 7.92 (m, 2H), 7.81-7.73 (m, 1H), 7.64 (m, 1H), 7.54 (m, 1H), 7.36 (dd, J=8.4, 2.8 Hz, 2H), 7.13 (dd, J=8.4, 2.8 Hz, 2H), 6.02 (d, J=1.6 Hz, 1H), 4.65 (d, J=2.0 Hz, 2H), 3.08 (s, 3H), 2.97 (s, 3H) ppm.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=[O:23])[CH2:15][CH2:14]1)=[O:11])(=O)C1C=CC=CC=1.[OH-].[Na+].C(O)C>O>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10]([NH2:9])=[O:11])[CH2:18][CH2:17]2)=[CH:25]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(CCCC(=O)c2c[nH]c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)NC1CCN(CCCC(=O)c2c[nH]c3ccccc23)CC1

Procedure:
1-Benzoyl-3-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea free base (2.9g), sodium hydroxide (0.54g), ethanol (15ml) and water (5ml) were refuxed for two hours and then poured into cold water, the precipitated solid was filtered off and crystallised from ethanol to give 1-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)[CH2:2][CH3:3].C[Si](Cl)(C)C.C1C=CC=CC=1.ClC1C=CC(C([C@@:30]2([OH:47])[C@@H:34]([CH:35](C(=O)C3C=CC(Cl)=CC=3)[OH:36])[O:33][CH:32](Cl)[CH2:31]2)=O)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH2:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[N:8]([CH:9]=1)[C@@H:32]1[O:33][C@H:34]([CH2:35][OH:36])[C@@H:30]([OH:47])[CH2:31]1)[CH2:2][CH3:3]
Reactant: O=C(c1ccc(Cl)cc1)C(O)[C@H]1OC(Cl)C[C@@]1(O)C(=O)c1ccc(Cl)cc1
Reactant: CCCc1c[nH]c(=O)[nH]c1=O
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [Hg+2]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 24 h
Yield: 166.5 %

Procedure:
To a solution of 15,4 g 5-propyluracil (0.1 mole) and 21,7 g trimethylsilyl chloride (0,2 mole) in 250 ml anhydrous benzene 20.2 g dry triethylamine (0,2 mole) are added dropwise under stirring and exclusion of humidity within a time span of 15 minutes. After further stirring for about 12 hours the unreacted 5-propyl-uracil and the precipitated dry ethylamine hydrochloride are separated and the filtrate is concentrated under vacuum. The residue is dissolved in 150 ml of absolute toluene and under stirring a solution of 43 g 3,5-di-(p-chlorobenzoyl)-2-desoxy-D-ribofuranosyl chloride (0,1 mole) in 500 ml toluene and thereafter 31,8 g mercury (II)-acetate are added and the stirring is continued another 24 hours. After filtration the filtrate is extracted with a 30% aqueous potassium iodide solution and thereafter washed with water. After drying over sodium sulfate the toluene solution is concentrated to approximately 100 ml. Upon standing the protected nucleoside crystallizes. 45 g of a product with melting point 140°-165° C. are obtained.
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][C:38]=3[C:44]([F:47])([F:46])[F:45])=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:50][CH2:51][N:52]([CH2:55][CH3:56])[CH2:53][CH3:54]>C(Cl)Cl.CO>[CH2:51]([N:52]([CH2:55][CH3:56])[CH2:53][CH2:54][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH3:50]
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-ylamino)-3-trifluoromethyl-phenol (Example 28) and using (2-chloroethyl)-diethylamine hydrochloride. The title compound: ES-MS: 441.9 [M+H]+; single peak at tR=3.41 min (System 2); Rf=0.25 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[C].[Pd].C1COCC1.CCO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(N)c(O)c1
Reaction time: 1 h

Procedure:
To the flask was added THF/EtOH (1:1, 30 mL) followed by Ethyl 2-(3-hydroxy-4-nitrophenyl)propanoate (900 mg, 3.76 mmol) and 10% palladium carbon (93 mg) at room temperature. The reaction mixture was hydrogenated and stirred for 1 hrs at 46 psi then filtered through celite bed, and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant.
Reaction SMILES: C([O:4][C:5](=[O:26])[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH2:23][CH2:24][Cl:25])[CH2:20][CH2:21][Cl:22])=[CH:18][C:11]=2[N:10]=1)(C)C.[ClH:27]>O>[CH3:14][N:13]1[C:9]([CH2:8][CH2:7][CH2:6][C:5]([OH:26])=[O:4])=[N:10][C:11]2[CH:18]=[C:17]([N:19]([CH2:20][CH2:21][Cl:22])[CH2:23][CH2:24][Cl:25])[CH:16]=[CH:15][C:12]1=2.[ClH:27]
Reactant: CC(C)OC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Agent: Cl
Solvent: O
Product: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Temperature: 42.5 °C
Reaction time: 1.5 h

Procedure:
4-{5-[Bis-(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid isopropyl ester (4 g), is added to a mixture of water (13.6 mL) and concentrated hydrochloric acid (5.4 mL) in a round bottom flask. The mixture is heated to 40-45° C., maintained for 8 hours. Cooled the reaction mass to 25-30° C., stirred for 90 minutes, filtered, washed with water (12 mL), and dried under vacuum of 500-600 mm of Hg at 29° C. for 3 hours to give bendamustine hydrochloride. Yield: 2.7 g (75%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.O.[C:12]([OH:16])(=[O:15])[CH:13]=O.C(=O)([O-])[O-].[K+:21].[K+]>CO>[C:9]([C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[CH:13][C:12]([O-:16])=[O:15])#[N:10].[K+:21]
Reactant: Cc1cccc(CC#N)c1
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cccc(C(C#N)=CC(=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (3-methylphenyl)-acetonitrile (21.6 ml, 165 mmol) in methanol (500 ml) were added glyoxylic acid hydrate (22.7 g, 247 mmol) and potassium carbonate (57.0 g, 412 mmol). The reaction mixture was stirred at room temperature for 2 hours followed by 3 hours at reflux. The precipitate was filtered off, washed with methanol (300 ml), dichloromethane (DCM) (300 ml) and then dried under air suction. The desired product was obtained as a white solid which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(OC([N-:32][S:33](N1C=CC(=[N+](C)C)C=C1)(=[O:35])=[O:34])=O)(C)(C)C>C(#N)C>[Cl:17][C:12]1[CH:11]=[C:10]([CH:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][CH:3]2[CH2:2][NH:1][S:33](=[O:35])(=[O:34])[NH2:32])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNS(N)(=O)=O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 117.6 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (144 mg) in acetonitrile (2 mL) was added N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (190 mg) prepared by the method described in Organic Letters, 2001, 3 (14), 2241-2243, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with 1 N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (205 mg).
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[O:22][CH3:23])[O:5][C:6]2=[O:13].[CH2:24]([SiH](CC)CC)C.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:24][C:10]1[CH:9]=[C:8]([O:11][CH3:12])[C:7]([C:6]([OH:5])=[O:13])=[C:3]([CH2:4][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH:2]=1
Reactant: CC[SiH](CC)CC
Reactant: COc1ccc(OC)c(C2OC(=O)c3c(OC)ccc(C)c32)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(OC)c(Cc2cc(C)cc(OC)c2C(=O)O)c1
Temperature: 25 °C

Procedure:
4-Methyl-7-methoxy-3-(2',5'-dimethoxyphenyl)-1-(3H)-isobenzofuranone (17 g) and triethylsilane (15 g) were dissolved in dichloromethane (200 ml) and stirred at room temperature under nitrogen. Titanium tetrachloride (5N in CCl4, 25 ml) was added by syringe. The reaction mixture was stirred at room temperature for 4 hours. Water (10 ml) was added dropwise and the reaction mixture was concentrated down. The resulting slurry was dissolved (with heating) in 2N NaOH (aq) and filtered through celite. The filtrate was washed with diethyl ether (2×200 ml) and acidified with concentrated HCl (aq). The resulting precipitate was collected by filtration and dried to give 4-methyl-6-methoxy-2-(2',5'-dimethoxybenzyl)benzoic acid, m.p. 172°-174° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[C:13](N)=[CH:14][C:15]([F:18])=[C:16](Br)[C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1.N1CCCCC1.[CH3:26][C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:30]#[C:29][C:27]([CH3:28])([OH:31])[CH3:26])[C:15]([F:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(C)O
Reactant: Nc1nccc(-n2cnc3c(Br)c(F)cc(N)c32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(C)(O)C#Cc1cc2c(cc1F)ncn2-c1ccnc(N)n1
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 26.7 %

Procedure:
To a pressure tube was added 3-(2-aminopyrimidin-4-yl)-7-bromo-6-fluoro-1,3benzodiazol-4-amine (66%, 250 mg, 0.54 mmol), piperidine (1.5 mL), tetrakis(triphenylphosphine)palladium (61.9 mg, 0.05 mmol), copper(I) iodide (10.2 mg, 0.05 mmol) and 2-methylbut-3-yn-2-ol (0.1 ml, 1.07 mmol). The reaction was stirred at 75° C. for 2.5 h before concentrating in vacuo. The crude product was purified by column chromatography (Biotage) eluted with DCM: methanol gradient (98:3 to 90:10). Material obtained triturated with methanol to obtain the title compound as an off-white solid. (45 mg, 26.7% yield); 1H NMR (500 MHz, DMSO) delta 1.52 (6H, s), 5.53 (1H, s), 7.14 (1H, d, J=5.20 Hz), 7.18 (2H, br. s.), 7.67 (1H, d, J=9.62 Hz), 8.40 (1H, br. s.), 8.63 (1H, d, J=6.62 Hz), 9.16 (1H, s); LC-MS m/z+312.5 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:9](=[O:23])[C:8]2=O)(=[O:3])[CH3:2].Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][N:16]([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:21])[CH3:22])[C:9](=[O:23])/[C:8]/2=[N:26]/[NH:27][C:28]([NH2:30])=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Reactant: NNC(N)=O
Agent: Cl
Product: CC(=O)Nc1ccc2c(c1)/C(=N\NC(N)=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 32 %

Procedure:
By using 5-acetamido-1-(2-diisopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out, and the reaction product was purified with silica gel column chromatography (eluent: chloroform/methanol=50/1) and then recrystallized from chloroform-hexane to obtain (E)-5-acetamido-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 135°-137° C. (yield: 32.0%).
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:4].[CH3:26][C:27]1[NH:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CC(OC)(C)C>[CH3:25][C:20]1[CH:19]=[C:18]([N:5]([CH2:6][CH2:7][C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C:3](=[O:4])[CH2:2][N:28]2[C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=[C:27]2[CH3:26])[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)CBr)cc1C
Reactant: Cc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CC#N
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)Cn2c(C)nc3ccccc32)cc1C
Yield: 57.6 %

Procedure:
A suspension of 2-bromo-N-(3,4-dimethyl-phenyl)-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (134 mg, 0.32 mmol), 2-methylbenzimidazole (85 mg, 0.65 mmol) and potassium carbonate (67 mg, 0.48 mmol) in acetonitrile (1 mL) was irradiated in the microwave for 20 min. at 140° C. The reaction mixture was diluted with TBME (15 mL) and washed with water (15 mL) and brine (15 mL). The aqueous layers were extracted with tert-butylmethylether (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:95:5) afforded the title compound (86 mg, 57%) as a light brown oil. MS m/e: 467.0 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:24]O>>[CH3:24][O:13][C:12](=[O:14])[C:11]([CH3:15])([CH3:16])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([NH2:1])[CH2:17][CH3:18]
Reactant: CO
Reactant: CCC(N)CCCCCCCCC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Product: CCC(N)CCCCCCCCC(C)(C)C(=O)OC
Yield: 89.5 %

Procedure:
51.4 g (0.2 mole) of 11-amino-2,2-dimethyl-tridecanoic acid and 200 ml of methanol and 22 g (0.224 mole) of sulfuric acid are refluxed for 3 hours. Excess methanol is then distilled off, the residue is diluted with about 200 ml of water and the reaction solution is made weakly alkaline (pH 8-10) with aqueous sodium hydroxide, whereupon the aminoacid ester separates as upper organic phase. Subsequent distillation yields 48.5 g (0.179 mole) of 11-amino-2-,2-dimethyl-tridecanoic acid methyl ester, corresponding to a yield of 89.5% of theory.