Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.[CH:17]1([C:20]2[C:21]([N:29]3[CH2:34][CH2:33][N:32]([C:35]([C:37]4[CH:42]=[CH:41][C:40](I)=[CH:39][C:38]=4[F:44])=[O:36])[CH2:31][CH2:30]3)=[N:22][CH:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[C:21]([N:29]3[CH2:30][CH2:31][N:32]([C:35]([C:37]4[CH:42]=[CH:41][C:40]([N:11]5[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]5(=[O:15])=[O:16])=[CH:39][C:38]=4[F:44])=[O:36])[CH2:33][CH2:34]3)=[N:22][CH:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=2)[CH2:18][CH2:19]1
Reactant: O=C(c1ccc(I)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: O=C(c1ccc(N2[C@H](CO)CCS2(=O)=O)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 43.6 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (393 mg) described in Preparation Example 1 and [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (800 mg) described in Preparation Example 164 and by the reaction and treatment in the same manner as in Example 32, the title compound (365 mg) was obtained.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7](=O)[CH2:8][CH3:9].O.S(=O)(=O)(O)O.[CH2:17]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]([CH3:20])[CH3:19]>>[CH3:19][CH:18]([CH3:20])[CH2:17][N:21]([CH:7]=[CH:8][CH3:9])[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CNCC(C)C
Reactant: CCC=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: CC=CN(CC(C)C)CC(C)C
Temperature: 12.5 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To a suspension of magnesium sulfate (15.1 g) in diisobutylamine (107.3 g) was added dropwise propionaldehyde (24.8 g) at 0-10° C. under a nitrogen atmosphere, and it was stirred at 10-15° C. for 1.5 hours. After ice-cooling, water (90 ml) was added and it was stirred to dissolve the magnesium sulfate. After the removal of the aqueous layer, to the organic layer obtained was added an 8% (w/v) aqueous sulfuric acid solution (300 ml) at 0-5° C. and then stirred for 10 minutes. The aqueous layer was, then, removed again, a 0.5% (w/v) aqueous sodium hydroxide solution (90 ml) was added to the organic layer at 0-5° C., and stirred for 10 minutes. After stirring, the aqueous layer was removed to afford the title compound (57.0 g, yield: 76%, purity: 96.7%) as a colorless oil.
Reaction SMILES: C([O-])(=O)CC[C@H](NC(C1C=CC(NC[C:17]2[CH2:18][NH:19][C:20]3[N:21]=[C:22]([NH:24][C:25]([C:27]=3[N:28]=2)=[O:26])[NH2:23])=CC=1)=O)C(O)=O.CN(C1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1)CC1C=NC2N=C(N)N=C(N)C=2N=1.C1C(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=C(NCC2C=NC3N=C(N)N=C(N)C=3N=2)C=1.NC1N=C(N)C(C2C=CC(Cl)=C(Cl)C=2)=C(C)N=1.CC1C2C(N)=NC(N)=NC=2C=CC=1CNC1C=C(OC)C(OC)=C(OC)C=1.CCC1N=C(N)N=C(N)C=1C1C=CC(Cl)=CC=1.COC1C=C(CC2C=NC(N)=NC=2N)C=C(OC)C=1OC.C1C2C(N=C(N)NC=2NCC1CCC1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1)=O>>[N:21]1[C:20]2[C:27](=[N:28][CH:17]=[CH:18][N:19]=2)[C:25](=[O:26])[NH:24][C:22]=1[NH2:23]
Reactant: Nc1nc2c(c(=O)[nH]1)N=C(CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc1)CN2
Agent: CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1
Agent: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Product: Nc1nc2nccnc2c(=O)[nH]1

Procedure:
When in the above examples, other dihydrofolate reductase inhibitors replace methotrexate, e.g. aminopterin or 10-propargyl-5,8-dideazafolate or 2,4-diamino,5-(3′,4′-dichlorophenyl),6-methylpyrimidine trimetrexate, or pyrimethamine or trimethoprim or pyritrexim 5,10-dideazatetrahydrofolate or 10-ethyl,10-deaza-aminopterin, similar results of pterin salvage pathway blocking are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[C:19]2[C:24]([F:27])([F:26])[F:25])(=[O:12])=[O:11])([O-])=O.Cl[Sn]Cl>Cl.CCO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[C:19]2[C:24]([F:27])([F:26])[F:25])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Yield: 81.7 %

Procedure:
In a similar fashion using route 1 general procedure 4, 2-nitro-N-(4-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 251) (0.4 g, 1.0 mmol), SnCl2 (0.76 g, 4.03 mmol), 6N HCl (2 drops) and EtOH (15 ml) gave the title compound (300 mg, 81%) which was used in the next step without further purification.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].CN(C)C=O.[NH2:22][C@H:23]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(N(CC)CC)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:22][C@H:23]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:9])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6.225 g. (25 mole) of BOC-L-Met was dissolved in 160 ml. of degassed dimethylformamide and cooled under nitrogen to 0° C. 4.55 g. (25 mmole) of L-Leu-OMe was dissolved in 80 ml. of dimethylformamide and set aside. To the BOC-L-Met was added 5.38 ml. of diphenylphosphorylazide in 10% excess followed by 3.48 ml. of triethylamine in 10% excess, followed by the L-Leu-OMe. The reaction mixture was stirred at 0° C. for 3 hrs., then at room temperature for 16 hrs. The solution was concentrated and treated with 3:1 dimethylformamide/water and mixed bed resin, whereupon it crystallized out on the resin. The resin and crystals were filtered and the resin washed with dimethylformamide to isolate the product. The filtrate was then concentrated and recrystallized from ethyl acetate/hexane. 7.74 g. of product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][Cl:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCOc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A mixture of 4-chlorophenol (100 g), 1-bromo-2-chloroethane (335 g), potassium carbonate (129 g) and acetone (2 l) was boiled under reflux with stirring for 18 hours. The mixture was evaporated to dryness under reduced pressure and then dichloromethane was added to the cool residue. The mixture was filtered and the filtrate washed with 5M sodium hydroxide solution, water, dried, filtered and evaporated to give 2-chloroethyl 4-chlorophenyl ether as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:16][CH2:17][CH2:18][CH3:19])[C:11]=1[O:12]CCC)[CH:7]=[O:8])([O-:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[OH:12][C:11]1[C:10]([O:16][CH2:17][CH2:18][CH3:19])=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CCCOc1cc(C=O)cc([N+](=O)[O-])c1OCCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCOc1cc(C=O)cc([N+](=O)[O-])c1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 3-nitro-4,5-dipropoxybenzaldehyde (153 mg, 0.573 mmol) in anhydrous CH2Cl2 (5 mL) was added anhydrous AlCl3 (151 mg, 1.15 mmol) at 0° C., after the addition, the reaction mixture was stirred at 50° C. for 1 hour. The reaction was quenched by water (20 mL), and the mixture was acidified with 2N aqueous HCl solution (20 mL), followed by a standard aqueous/EtOAc workup. Purification by column chromatography gave Intermediate 65 (126 mg, yield: 97.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH:15]=3)[N:10]([CH3:23])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:26]>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:21])([CH3:22])[C:19]([OH:26])=[O:20])[CH:15]=3)[N:10]([CH3:23])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)CO)ccc2n1C
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Reaction time: 8 h

Procedure:
A solution of 6.0 g (60 m mole) of chromium trioxide in 50 ml of glacial acetic acid and 5 ml of water was added dropwise to a mixture of 19.0 g (55 m mole) of 2-[3-(4-chloro-phenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methylpropanol, 50 ml of glacial acetic acid, 10 ml of water, and 5 ml of conc. sulfuric acid under stirring. After standing overnight, the reaction mixture was warmed for one hour on a steam bath. Subsequently the mixture was extracted with chloroform. The chloroform extracts were dried, and the evaporation residue was chromatographed on silicagel with chloroform/methanol (8:2) as eluant.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[C:30](=O)[CH3:31].C([BH3-])#N>[Zn]>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:30]([C:22]3[S:21][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH3:31])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CC(=O)c1nc2ccccc2s1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [BH3-]C#N
Agent: [Zn]
Product: CC(Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1)c1nc2ccccc2s1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 1-benzothiazol-2-yl-ethanone with zinc-modified cyanoborohydride yielded a mixture of epimers of the title compound as a colorless solid. MS (ESI): m/z=440.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.[OH-].[Na+]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: CCOC(=O)CCCCn1c(CCOC)nc2cnc3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Product: COCCc1nc2cnc3ccccc3c2n1CCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Ethyl 5-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanoate (15.1 g, 42.4 mmol) was treated with sodium hydroxide (2.20 g, 55.2 mmol) according to the method described in Part A of Example 11. The reaction was stirred overnight at ambient temperature to provide 10.2 g of 5-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanoic acid after the aqueous work-up procedure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[Al+3].[Cl-].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:14](=[O:15])[NH:13][S:10](=[O:12])(=[O:11])[C:3]=2[CH:4]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: Cc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
p-Toluidine (11.00 g, 102.65 mmol) dissolved in nitromethane (50 mL) was added slowly over 20 minutes to a solution of chlorosulfonyl isocyanate (16.89 g, 119.40 mmol) in nitromethane (160 mL) at −5° C. The suspension was stirred at −5° C. for an additional 15 minutes and AlCl3 (17.00 g, 129.00 mmol) was added portionwise. The reaction mixture was then heated at 105° C. for 30 minutes. The hot solution was poured onto ice (1 L) and the resulting precipitate was filtered off and washed with water (300 mL). The solid was then dissolved in a hot aqueous sodium bicarbonate solution (10 g/200 mL), treated with charcoal, and filtered. The cooled solution was neutralized using 6N HCl and the resulting white precipitate was filtered off, washed with water and dried to afford the title compound (14 g, 64%).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=3[C:13]([CH3:21])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](OCC)=[O:33])=[CH:30][N:31]=[C:25]2[CH:24]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][N:26]2[C:29]([C:32]([NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[C:13]([CH3:21])=[N:12][N:11]4[CH2:10][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:9]=3)=[O:33])=[CH:30][N:31]=[C:25]2[CH:24]=1
Reactant: CCOC(=O)c1cnc2cc(F)ccn12
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Temperature: 0 °C
Yield: 73 %

Procedure:
1-((6-Isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine (Preparation D; 0.673 g, 2.40 mmol) and ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (Step C, 0.500 g, 2.40 mmol) were dissolved in dry THF (24 mL) and chilled to 0° C. LiHMDS (5.28 mL, 5.28 mmol, 1M in THF) was added by syringe over a five-minute period. Once the addition was complete, the reaction mixture was removed from the cooling bath and allowed to warm to ambient temperature. The mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated. The crude material was purified by column chromatography (100% ethyl acetate) to afford 775 mg (73%) of 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[CH3:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH:16][CH2:23][C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Reactant: Cc1ccc(C=O)o1
Agent: [Cl-]
Product: Cc1ccc(CNCCOc2ccc3ccccc3c2F)o1
Yield: 63 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and 5-methylfuran-2-carbaldehyde in 63% yield as a yellow oil. 1H-NMR (CD3OD) δ: 8.00 (1H, d), 7.88-7.84 (1H, m), 7.70 (1H, d, J=8.88 Hz), 7.55 (1H, ddd, J=1.2 Hz, J=6.88 Hz, J=8.50 Hz), 7.46 (1H, ddd, J=1.88 Hz, J=6.88 Hz, J=8.2 Hz), 7.41 (1H, d, J=8.88 Hz), 6.50 (1H, d, J=3.31 Hz) 6.14 (1H, qd, J=0.9 Hz, J=3.31 Hz) 4.47 (2H, t, J=5.00 Hz), 4.41 (2H, s) 3.50 (2H, t, J=5.00 Hz), 2.31 (3H, d, J=0.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.[BH4-].[Na+].CO.OS(O)(=O)=O>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[CH2:6]2
Reactant: CC1Cc2c(Br)ccc(Br)c2C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=Cc2c(Br)ccc(Br)c2C1
Reaction time: 3 h
Yield: 98.4 %

Procedure:
In a 250 ml round bottom flask 19.2 g (63 mmol) 4,7-Dibromo-2-methyl-indan-1-one were dissolved in 70 ml of toluene at 50° C. Then 2.63 g (1.1 eq.) sodium borohydride were added. At 50° C. 11 ml (4.3 eq.) methanol were added dropwise over a period of 30 min. Stirring was continued at 50° C. for 3 h (complete conversion) and then 50 ml water and 50 ml of 2M H2SO4 were added. The aqueous phase was extracted 2 times with 100 ml toluene. The combined organic layers were washed with 50 ml 2M H2SO4 and 50 ml of a sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo. 200 ml toluene and 200 mg p-toluene sulfonic acid were added and the solution was heated on a Dean-Stark-trap for 90 min. 50 ml of a saturated sodium bicarbonate solution were added. The aqueous layer was extracted 2 times with 50 ml toluene each. The combined organic layers were washed with 50 ml of a saturated sodium bicarbonate solution and 50 ml of a sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo to yield 17.8 g (62 mmol, 98%) of the desired indene as a slightly brown oil. 1H-NMR (500 MHz, CDCl3): δ=7.48, 7.35 (2×d, 2H, aromatic), 6.49 (s, 1H, indenyl-C═CH), 3.32 (s, 2H, benzylic), 2.12 (2, 3H, CH3) ppm.
Reaction SMILES: [CH2:1]([N:4]([CH3:16])[CH2:5][C:6]#[C:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH:26]1[C:31]([O:32][C:33](Cl)=[O:34])=[CH:30][CH:29]=[C:28]([Cl:36])[CH:27]=1>O1CCOCC1.C([O-])(O)=O.[Na+].CCOCC>[Cl:36][C:28]1[CH:29]=[CH:30][C:31]([O:32][C:33](=[O:34])[N:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([C:7]#[C:6][CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:16])[CH2:9][CH2:10]2)[CH3:15])=[CH:26][CH:27]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: C=CCN(C)CC#C[C@H]1CC[C@H](NC)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C)CC#C[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Reaction time: 0.08 h

Procedure:
A solution of 66 mg (0.3 mmol) of trans-{4-[3-(Allyl-methyl-amino)-prop-1-ynyl]-cyclohexyl}-methyl-amine in 0.3 ml dioxane was treated with 0.103 ml (0.6 mmol; 2 equivalents) Huenig's base and dropwise with a solution of 0.042 ml (0.27 mmol) 4-chlorophenylchloroformate in 0.16 ml dioxane (during 10 min). After 5 min at RT, the mixture was dissolved in aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried over Na2SO4 and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (99:1 to 97:3) yielded 68 mg (61%) of trans-{4-[3-(Allyl-methyl-amino)-prop-1-ynyl]-cyclohexyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 375 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]1([C:22]2[O:23][C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH2:21][CH2:20]1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]4[CH2:20][CH2:21]4)[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1nc(C2CC2)oc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C4CC4)oc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1
Reactant: Cc1cc(C(=O)O)nc(N)n1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)nc(N)n1
Yield: 52 %

Procedure:
The title compound is prepared in 52% yield (146 mg, clear pale yellow oil) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (210 mg, 0.72 mmol, Amine-5, single enantiomer) and 2-amino-6-methylpyrimidine-4-carboxylic acid (110 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH2:17]Cl)=[N:15][N:16]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:27][NH:28][CH3:29].[I-].[Na+]>>[CH3:27][N:28]([CH2:17][C:14]1[N:13]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[N:10][CH2:11][C:12]2=[N:16][N:15]=1)[CH3:29]
Reactant: COc1cccc2c1C(c1cccc(SC)c1)=NCc1nnc(CCl)n1-2
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Product: COc1cccc2c1C(c1cccc(SC)c1)=NCc1nnc(CN(C)C)n1-2

Procedure:
In the manner given in Example 1, 7-methoxy-1-(chloromethyl)-6-[m-(methylthio)phenyl]-4H-s-triazolo-[4,3-a][1,4]benzodiazepine was reacted with dimethylamine in the presence of sodium iodide to give 1-[(dimethylamino)methyl]-7-methoxy-6-[m-(methylthio)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:3][CH:2]=1.[N+:22]([O-])([OH:24])=[O:23]>S(=O)(=O)(O)O>[N+:22]([C:19]1[CH:20]=[CH:21][C:8]([NH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:9]([CH:18]=1)[C:10]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:11])([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccccc1Nc1ccncc1)N1CCCCC1
Agent: O=S(=O)(O)O
Product: O=C(c1cc([N+](=O)[O-])ccc1Nc1ccncc1)N1CCCCC1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
To a solution of 20 g of 1-[2-(4-pyridinylamino)benzoyl]piperidine (Example 1b) in 75 ml of sulfuric acid cooled in an ice-salt bath was slowly added a solution of 6.5 ml of concentrated nitric acid in 65 ml of sulfuric acid. The mixture was stirred at 5° C. for four hours and then poured onto ice and allowed to stand overnight. A crystalline acid-addition salt formed which was collected, dissolved in water and converted to the free base by adding sodium bicarbonate. The free base product was extracted with methylene dichloride, the extracts dried over anhydrous sodium sulfate and concentrated, and the residue triturated with ethyl acetate to give 9.3 g of 1-[5-nitro-2-(4-pyridinylamino)benzoyl]piperidine as a yellow powder, m.p. 194°-196° C.(decompn.).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 4-methyl-benzoyl chloride (0.46 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was triturated in Et2O (50 mL) for 18 h then filtered and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methyl-benzamide as a white solid (0.85 g, 70% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.48 min (96.54%); mp: 194-196° C.; 1H NMR (DMSO-d6) δ 1.97-2.14 (m, 1H, CHH), 2.36 (s, 3H, CH3), 2.44-2.71 (m, 2H, M01), 2.78-3.04 (m, 1H, CHH), 4.63 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.30 (d, J=7.9 Hz, 2H, Ar), 7.75-7.86 (m, 4H, Ar), 7.90 (d, J=7.6 Hz, 1H, Ar), 9.14 (t, J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.96, 21.99, 30.93, 42.57, 49.01, 121.95, 123.53, 127.27, 128.91, 129.77, 131.14, 131.60, 133.42, 141.37, 147.73, 166.30, 166.99, 167.13, 169.80, 172.72; LCMS: MH=406; Anal Calcd for C22H19N3O5+0.1H2O: C, 64.89; H, 4.75; N, 10.32. Found: C, 64.72; H, 4.70; N, 10.15.