Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[CH3:28][S:29]([O:1][CH:2]1[CH2:5][N:4]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[CH2:3]1)(=[O:31])=[O:30]
Reactant: O=C1CCCCN1c1ccccc1CCN1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OC1CN(CCc2ccccc2N2CCCCC2=O)C1
Reaction time: 2 h

Procedure:
To 1-{2-[2-(3-hydroxyazetidin-1-yl)ethyl]phenyl}piperidin-2-one a11-1 (212 mg, 0.77 mmol, 1 eq) in dichloromethane (15 ml) under nitrogen is added triethylamine (216.04 μl, 1.55 mmol, 2 eq). Methanesulfonyl chloride (106.53 mg, 0.93 mmol, 1.2 eq) is added at 0° C. and the reaction mixture is allowed to reach room temperature while stirring for 2 hours under a nitrogen atmosphere. Additional triethylamine (216 μl, 1.55 mmol, 2 eq) and methanesulfonyl chloride (106.53 mg, 0.93 mmol, 1.2 eq) are added, and the reaction mixture stirred at room temperature under nitrogen for an additional hour. Water (50 ml) is then added, the two phases vigorously shaken and separated. The organic phase is dried over MgSO4, filtered and evaporated to dryness to give 1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}azetidin-3-yl methanesulfonate a11-2 which is used in next step without any further purification.
Reaction SMILES: [F:1][C:2]1[C:25]([OH:26])=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[N:22]O)[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.C(O)(=O)C>C(O)C.O.[Zn]>[F:1][C:2]1[C:25]([OH:26])=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]([NH2:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(F)c(O)cc2[nH]1
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NC1c2ccccc2-c2c(-c3nc4cc(F)c(O)cc4[nH]3)cccc21

Procedure:
The procedure used in stage 4 of Example 216 is followed. In a 30 ml round-bottomed flask under an argon atmosphere, dissolve 667 mg of equimolecular mixture of 4-(5-fluoro-6-hydroxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 3.5 ml of ethanol and 3.5 ml of water and 3.5 ml of acetic acid; at room temperature, add 500 mg of zinc in three stages. Between each addition, stir for approximately one hour to two hours. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (9/1 then 85/15 by volume), in this way we obtain 456 mg of 4-(5-fluoro-6-hydroxy-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a beige powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:11])[C:7]=1[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][N:54]1[CH:58]=[CH:57][C:56]([NH2:59])=[N:55]1>CN(C)C=O>[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][N:54]1[CH:58]=[CH:57][C:56]([NH:59][C:8]([C:7]2[C:6]([F:11])=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[O:10])=[N:55]1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
Reactant: O=C(O)c1c(F)cncc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2Cl)n1)c1c(F)cncc1F
Reaction time: 0.08 h
Yield: 114.8 %

Procedure:
To a solution of 3,5-difluoro-4-pyridinecarboxylic acid (15.9 mg, 0.1 mmol, Frontier Scientific) in dimethylformamide (0.1 ml) was added HATU (38 mg, 0.1 mmol) in dimethylformamide (0.2 mL), followed by N,N-diisopropylethylamine (0.050 ml, 0.286 mmol) and the resulting solution left for 5 min. Finally, a solution of 1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-3-amine (24.2 mg, 0.01 mmol, ChemCollect GmbH) in N,N-dimethylformamide (0.1 ml) was added and the resulting solution shaken for 10 min. The solution was then left to stand for 16 h at ambient temperature after which the solvent was removed. A 1:1 mixture of dimethylsulphoxide:methanol (0.6 ml) was added and the solution purified by MDAP on SUNFIRE C18 column (Method D). The appropriate fraction was concentrated in vacuo then under nitrogen flow to give the title compound (4.4 mg);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.CCN(CC)CC>CO.C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cccnc1
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a stirred solution of the aniline produced in Example 2 (82 mg, 0.32 mmol) in MeOH (3 mL) and THF (1 mL) was added 4-chlorobenzenesulfonyl chloride (74 mg, 0.35 mmol) followed by Et3N (89 μL, 0.64 mmol). After 20 minutes an additional amount of MeOH (1 mL) was added to aid in dissolving the reagents and the reaction mixture was allowed to stir overnight. At this time, the solvent was removed and the residue was dissolved into CH2Cl2. The resulting solution was washed three times with water and once with brine. The organic layer was evaporated and the resulting residue was purified by chromatography (1:1 hexane/diethyl ether) to provide 43.6 mg of the title compound (32% yield).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]([CH3:26])[S:10]([C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])(=[O:12])=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:27]1([CH3:33])[CH:32]=CC=[CH:29][CH:28]=1>>[CH2:29]=[CH:28][C:27](=[CH2:32])[CH3:33].[C:1]([O:6][CH2:7][CH2:8][N:9]([CH3:26])[S:10]([C:13]([F:25])([F:24])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:19])[F:18])(=[O:11])=[O:12])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Cc1ccccc1
Agent: C=C(C)C(=O)OCCN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: C=CC(=C)C

Procedure:
The materials flowed through the first three zones facilitated by stirring paddles along the reaction path. Polymerization continued to substantially 100% completion by the end of zone 4, thereby forming a “living” polyisoprene reaction mixture. At the start of zone 4, the solution of diphenylethylene in cyclohexane, solids of about 12 wt %, was added by a reciprocating piston pump (at a rate of 10.0 ml/min) to the “living” polyisoprene reaction mixture. This resulted in addition of a diphenylethylene-modified polyisopropenyl chain. This chain was treated at the start of zone 5 with a purified solution of 2-(N-methylperfluorobutanesulfonamido)ethyl methacrylate in toluene, solids of 20 wt % (fed by a reciprocating piston pump at rates of 2 and 10 ml/min) to form poly(isoprene-2-(N-methylperfluorobutanesulfonamido)ethyl methacrylate) block copolymers. The overall solids content of these reactions was about 32 wt %. The total residence time for these reactions was about 25 minutes.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[OH-:10].[Na+:11]>O>[OH2:3].[OH2:10].[C:1]([O-:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[Na+:11]
Reactant: [OH-]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)C[C@H](O)C(=O)[O-]
Temperature: 10 °C
Reaction time: 4 h
Yield: 120.8 %

Procedure:
26.8 g (0.20 mole) of L-malic acid and 8.0 g (0.20 mole) of sodium hydroxide are dissolved in 200 ml of water. The solution (pH 4.1) is concentrated under reduced pressure to make the total weight thereof 60 g. The concentrated solution is cooled to 10° C., and the mixture obtained (i.e., the mixture of the concentrated solution and crystals precipitated) is stirred at the same temperature for 4 hours. After stirring, the mixture had a pH of 4.1. The crystalline precipitates are collected by filtration, washed with an aqueous 80% methanol solution, and dried at 35° C. in air for 16 hours. 23.2 g of monosodium L-malate dihydrate are obtained as crystals. The amounts of L-malic acid, sodium and water contained in the product are shown in Table 5. The results set forth in this table indicate that the product obtained is the pure crystals of monosodium L-malate dihydrate.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:12][C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([OH:27])=O)(=[O:18])=[O:17])=[O:14])[N:3]=1.[CH3:28][Li].O.Cl>O1CCCC1.CCOCC.C(Cl)Cl>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[S:16]([NH:15][C:13]([NH:12][C:4]1[N:3]=[C:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:14])(=[O:18])=[O:17])(=[O:27])[CH3:28]
Reactant: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)nc2ccccc12
Reactant: [Li]C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2ccccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture containing 0.86 g of N-[(4-methylquinazolin-2-yl)aminocarbonyl]-2-carboxybenzenesulfonamide in 50 ml of anhydrous tetrahydrofuran is treated with 40 ml of a 1.4 M solution of methyllithium in ether at 25° under a nitrogen atmosphere. The mixture is stirred for 4 hours at ambient temperature and then poured into 500 ml of water containing 10 ml of concentrated hydrochloric acid. The product can be isolated by extraction into methylene chloride followed by evaporation and if necessary, can be purified by preparative thin layer chromatography and/or recrystallization.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][CH2:12][CH:11]([CH2:16][C:17](OCC)=[O:18])[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][CH2:12][CH:11]([CH2:16][CH2:17][OH:18])[C:10]=3[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1CCCc2c1cnn2-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1CCCc2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.6 %

Procedure:
A solution of ethyl 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetate (1.40 g, 5.79 mmol) in 5 mL of THF is added over an aluminium-lithium hydride stirred suspension (300 mg, 7.9 mmol) in 20 mL of THF at room temperature. The mixture is maintained under stirring at room temperature for 18 hours and is afterwards refluxed during 1 hour. The mixture is hydrolyzed with ice and NaOH (10%), filtered through Celite and the solvent is evaporated under reduced pressure, to obtain 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)ethanol (1.10 g, 4.55 mmol, 79%, oil)
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Cc1cc2c(NCCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[F:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH:25]2[CH2:28][NH:27][CH2:26]2)=[CH:22][CH:21]=1>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:27]2[CH2:28][CH:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:30][CH:29]=3)[CH2:26]2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OC2CN(c3ccnc(Cl)n3)C2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To 2,4-dichloropyrimidine (200.0 mg, 1.342 mmol) in 2-propanol (7 mL) at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (0.702 mL, 4.03 mmol) followed by 3-(4-fluorophenoxy)azetidine hydrochloride (273 mg, 1.342 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min then at RT for 41 h and concentrated. Purification of the crude product was done using MPLC (25 g cartridge, 40 g column, 0 to 60% EtOAc-hexanes) to give 2-chloro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidine (314.2 mg).
Reaction SMILES: [C:1]1([C:7]2[C:8]([OH:29])=[C:9]([C:24]([O:26]CC)=O)[C:10]([CH:19]([O:22][CH3:23])[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[C:1]1([C:7]2[C:8]([OH:29])=[C:9]([C:24]([NH:30][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)=[O:26])[C:10]([CH:19]([O:22][CH3:23])[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(C(CC)OC)nc(-c2ccccc2)c(-c2ccccc2)c1O
Reactant: Nc1nccs1
Product: CCC(OC)c1nc(-c2ccccc2)c(-c2ccccc2)c(O)c1C(=O)Nc1nccs1
Yield: 81.7 %

Procedure:
Using the procedure of Example 5, 9.3 g of the product of Step E and 12 g of 2-aminothiazole were reacted to obtain 8.65 g of the expected product which after crystallization from ether melted at 236° to 238° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[CH:16][N:8]([C@@H:9]2[O:15][C@H:12]([CH2:13][OH:14])[CH:11]=[CH:10]2)[C:7](=[O:18])[N:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:4][C:5]1[CH:17]=[CH:16][N:8]([C@@H:9]2[O:15][C@H:12]([CH2:13][OH:14])[CH2:11][CH2:10]2)[C:7](=[O:18])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Yield: 77.7 %

Procedure:
A solution of 33 (0.78 g, 3.1 mmol) in ethanol (100 mL) was hydrogenated under 15 psi of hydrogen gas in the presence of 10% Pd/C (0.15 g) for 12 hours. The reaction mixture was filtered, concentrated, and the residue was purified by chromatography over silica using 5% methanol in CHCl3 as the eluent to obtain 0.61 g (77.5%) of 34 as a colorless solid: mp 143°-145° C. (benzene-methanol); 1H NMR (DMSO-d6) δ 1.60-2.50 (7H, m, 2',3'-H and COCH3), 3.40-3.85 (2H, m, 5'-H), 3.90-4.30 (1H, m, 4'-H), 5.07 (1H, t, J=5.0 Hz, OH), 5.91 (1H, m, 1'-H), 7.17 (1H, d, J=7.6 Hz, 5-H), 8.32 (1H, d, J=7.3 Hz, 6-H), 10.80 (1H, s, NH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[CH:6][CH:5]=1.C=O.[CH:26](O)=O>C(O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH3:22])[CH3:26])=[CH:6][CH:5]=1
Reactant: O=CO
Reactant: CCCN(CCC)CCCCNCc1ccc(C(=O)OC)cc1
Agent: C=O
Solvent: CCO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(C(=O)OC)cc1

Procedure:
The compound (310 mg) obtained in Example 88-1 was dissolved in ethanol (4.5 ml) and added with a 36% formaldehyde aqueous solution (150 μl) and formic acid (175 μl) and the whole was refluxed for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (234 mg) as a colorless oily substance.
Reaction SMILES: Cl.[CH:2]1([NH:5][CH:6]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:16]C)[O:8][CH2:7]2)[CH2:4][CH2:3]1.B(Br)(Br)Br.N>C(Cl)Cl>[CH:2]1([NH:5][CH:6]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[OH:16])[O:8][CH2:7]2)[CH2:4][CH2:3]1
Reactant: COc1cccc2c1CC(NC1CC1)CO2
Agent: BrB(Br)Br
Agent: Cl
Agent: N
Solvent: ClCCl
Product: Oc1cccc2c1CC(NC1CC1)CO2
Temperature: -20 °C
Yield: 86.4 %

Procedure:
3-(N-Cyclopropylamino)-5-metoxychroman hydrochloride (5.6 g, 22 mmol) was suspended in CH2Cl2 (140 mL) under N2. The mixture was cooled on a dry-ice/EtOH bath to -20° C. BBr3 (4.1 mL, 44 mmol) dissolved in CH2Cl2 (60 mL) was added to the stirred mixture during 0.5 hour. the yellow clear solution was slowly warmed to 0° C. and kept at that temperature until GC indicated a complete reaction (after 3-5 hours). Then the solution was poured on crushed ice (200 g) and enough conc. NH3 (aq.) to make a pH of 8-9. The mixture was extracted with ether (3×200 mL). The collected ether phases were dried (MgSO4), filtered and concentrated in vacou to afford a white solid. Crystallization from absolute EtOH afforded 3-(N-cyclopropylamino)-5-hydroxychroman (3.9 g, 88% yield) as colourless needles.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[C:12]1[CH:13]=[C:14]([CH3:28])[C:15]([C:18]2[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH:19]=2)=[N:16][CH:17]=1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].C([N+:52](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.O1CCCC1>[O:25]1[C:21]2([CH2:26][CH2:27][C:18]([C:15]3[N:16]=[CH:17][C:12]([NH2:52])=[CH:13][C:14]=3[CH3:28])=[CH:19][CH2:20]2)[O:22][CH2:23][CH2:24]1
Reactant: Cc1cc(Br)cnc1C1=CCC2(CC1)OCCO2
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N)cnc1C1=CCC2(CC1)OCCO2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
1.0M Toluene-solution of lithium bis(trimethylsilyl)amide (13.4 ml) was added at room temperature under nitrogen atmosphere to a solution of 5-bromo-2-(1,4-dioxaspiro[4,5]decane-7-ene-8-yl)-3-methylpyridine (2.78 g) of Reference Example 105, bis(dibenzylideneacetone) palladium (0) (258 mg) and tri-tert-butylphosphine tetrafluoroborate (130 mg) in toluene (12 ml), and stirred at 70° C. for two hours. Then, the reaction solution was cooled to room temperature, 1.0M tetrahydrofuran-solution of tetrabutylammonium fluoride (40.3 ml) was added and stirred at the same temperature for an hour. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with basic silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (773 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N-:34]=[N+]=[N-].[Na+].CN[C@@H]1CCCC[C@H]1NC.[NH4+].[Cl-].[OH-].[NH4+].CP(C)C>C1COCC1.O.[Cu]I.CCOC(C)=O>[NH2:34][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
A sealable vial was charged with (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (4h, 585 mg, 1.647 mmol), sodium L-ascorbate (Acros; 32.6 mg, 0.165 mmol), sodium azide (Aldrich; 321 mg, 4.94 mmol), and copper(I) iodide (Aldrich; 94 mg, 0.494 mmol). The vial was evacuated and backfilled with Argon. EtOH (5.0 mL) and water (2.1 mL) were added, the reaction mixture purged with Argon, and then treated with N,N′-dimethyl-trans-1,2-cyclohexanediamine (Aldrich; 52.0 μL, 0.330 mmol). The reaction mixture was heated to 80° C. for 5 h and then stirred at ambient temperature for 16 h. A mixture of saturated aqueous NH4Cl and concentrated ammoniumhydroxide (5 mL; 9:1) was added, followed by EtOAc (10 mL). After 30 min, the reaction mixture was poured into a mixture of saturated aqueous NH4Cl/concentrated ammoniumhydroxide (50 mL; 9:1) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to give a brown foam, which was dissolved in THF/water (8 mL; 3:1) and treated with trimethylphosphine (Aldrich; 1.0 M in THF) (2.0 mL, 2.000 mmol). The reaction mixture was stirred for 2 days and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (Gradient: 0%→10% MeOH/CH2Cl2) to give (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (419 mg, 1.439 mmol) as a white foam. MS m/z=292.1 [M+H]+. Calculated for C12H13F4N3O: 291.2
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12.[NH2:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.CCOC(C1C(=O)CCCC1)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu]Cl>[NH2:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12
Reactant: COC(=O)c1cc2nccc(Cl)c2s1
Reactant: Nc1cccc(O)c1
Agent: Cl[Cu]
Agent: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COC(=O)c1cc2nccc(Oc3cccc(N)c3)c2s1
Temperature: 70 °C

Procedure:
A mixture of methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (500 mg, 2.20 mmol), 3-aminophenol (330 mg, 3.0 mmol), ethyl 2-cyclohexanonecarboxylate (73 mg, 0.43 mmol), copper(I) chloride (22 mg, 0.22 mmol) and cesium carbonate (1.48 g, 4.55 mmol) in 20 ml of anhydrous DMSO was placed in a 50 ml pressure tube, flushed with nitrogen, sealed and heated at 70° C. for 3 hours. The mixture was cooled to room temperature and poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give crude methyl 7-(3-aminophenoxy)thieno[3,2-b]pyridine-2-carboxylate as brown solid. Yield: 330 mg.
Reaction SMILES: [ClH:1].CCOCC.C(OC(=O)[NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:34])[N:18]([C:25]1([CH3:33])[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])(C)(C)C>C(OCC)(=O)C>[ClH:1].[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:34])[N:18]([C:25]1([CH3:33])[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24]
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1(N2C(=O)c3cccc(CN)c3C2=O)CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
2N HCl/ether solution (8.5 mL) was added to a stirred solution of [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamic acid t-butyl ester (2.3 g, 5.7 mmol) in ethyl acetate (20 mL). The mixture was stirred at room temperature overnight. The mixture was filtered, and the solid was dried to gave 4-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.6 g, 80%) as a white solid: 1H NMR (DMSO-d6) δ 1.90 (s, 3H, CH3), 2.08 (m, 1H), 2.61-2.71 (m, 3H), 4.44 (M, 2H, CH2), 7.87-7.95 (m, 3H, Ar), 8.62 (s, 3H, NH3), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.97, 28.52, 29.04, 36.98, 58.77, 123.14, 128.38, 131.10, 132.28, 134.64, 135.58, 167.31, 168.00, 171.93, 172.09.