Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:8])[C:4]([CH3:7])([OH:6])[CH3:5].CCN(C(C)C)C(C)C.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1>CN1CCCC1=O.O>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:2][C@@H:3]([CH3:8])[C:4]([CH3:7])([OH:6])[CH3:5])[N:24]=2)=[CH:31][CH:30]=1
Reactant: C[C@H](N)C(C)(C)O
Reactant: COc1ccc(Nc2ccnc(Cl)n2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(Nc2ccnc(N[C@@H](C)C(C)(C)O)n2)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
(3S)-3-Amino-2-methyl-butan-2-ol HCl (1.00 mg, 7.16 mmol; prepared using the method of Konno et. al., Chem. Pharm. Bull. 1997, 45, 185) is dissolved in N-methyl-pyrrolidinone (10 mL). Hunig's base (1.62 mL, 9.30 mmol) is added followed by (2-chloropyrimidin-4-yl)-(4-methoxyphenyl)-amine, 1, (789 mg, 3.35 mmol) and the solution warmed to 140° C. After 24 hours, the reaction mixture is cooled to room temperature and diluted with water (100 mL) and the mixture extracted three times with CH2Cl2 (100 mL). The combined organic layers are washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified over silica (100% CH2Cl2 to 5% to 10% MeOH/CH2Cl2) to afford 564 mg (46% yield) of the desired product as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=5.8 Hz, 1H), 7.20 (d, J=9.0 Hz, 2H), 6.87 (d, J=9.0 Hz, 2H), 5.87 (d, J=5.8 Hz, 1H), 4.00-3.90 (m, 1H), 3.80 (s, 3H), 2.83 (s, 3H), 1.25 (s, 3H), 1.18 (d, J=7.3 Hz, 3H), 1.17 (s, 3H); MS (ESI) m/z 303 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=2)[O:20][C:21]=1[CH3:22])C.[Li+].[OH-].Cl>O1CCOCC1>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][N:11]3[C:12]4[C:8](=[C:7]([CH2:6][CH:5]([O:33][CH2:34][CH3:35])[C:4]([OH:36])=[O:3])[CH:15]=[CH:14][CH:13]=4)[CH:9]=[CH:10]3)[N:18]=2)[CH:24]=[C:25]([O:31][CH3:32])[CH:26]=1
Reactant: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2cc(OC)cc(OC)c2)oc1C)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(Cc1cccc2c1ccn2Cc1nc(-c2cc(OC)cc(OC)c2)oc1C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
rac-3-{1-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid ethyl ester (0.390 g, 0.79 mmol ) was dissolved in 15 ml of dioxane; 1.98 ml of an aqueous solution of LiOH (1.0 molar, 1.98 mmol) were then added at room temperature. The resulting mixture was stirred overnight at room temperature and then poured onto ice, neutralized to pH 4 with HCl (1N) and extracted 3 times with MeCl2. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 0.242 g (66 %) of rac-3-{1-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: [Br:1][CH:2]([C:6]1[N:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:10]=1)[C:3]([OH:5])=O.[CH:23]([C:26]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH2:28])([CH3:25])[CH3:24].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:26]([CH:23]([CH3:25])[CH3:24])[C:27]=1[NH:28][C:3](=[O:5])[CH:2]([C:6]1[N:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:10]=1)[Br:1])([CH3:35])[CH3:34]
Reactant: CCCCCCCCCCCCn1nnc(C(Br)C(=O)O)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCn1nnc(C(Br)C(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
To a solution of α-bromo-2-dodecyltetrazoleacetic acid (5.0 g, 13.3 mmol) in dichloromethane (75 mL), cooled to -10° C., were added 2,6-diisopropylaniline (2.3 g, 12.9 mmol) and DCC (2.7 g, 13 mmol), respectively. The suspension was gradually warmed to room temperature and was stirred for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo leaving a yellow liquid. The crude product was purified using silica gel chromatography (elution with 10% ethyl acetate/90% hexane) to give (±)-N-(2,6-diisopropylphenyl) -2-(2-dodecyl-2H-tetrazol-5-yl)-2-bromo-acetamide (4.8 g, 65% ) as a colorless liquid which crystallized on standing;
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)F.[Na+]>S(=O)(=O)(O)O>[CH3:2][CH2:3][CH2:4][CH2:5][O:1][C@H:4]([CH2:5][OH:1])[CH2:3][CH3:2]
Reactant: C1CCOC1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCO[C@@H](CC)CO
Temperature: -10 °C

Procedure:
In the same reaction apparatus as in Example 1, to 500 g of tetrahydrofuran was dropwise added, while maintaining the same at -10° C., a solution prepared by dissolving 0.75 g of sodium borofluoride in 105 g of 25% fuming sulfuric acid over a period of 40 minutes. After completion of this dropwise addition, the mixture was further subjected to reaction at -10° C. for one hour. The conversion of tetrahydrofuran in this reaction was 40%. Then, the reaction mixture was heated to 30° C. and further reacted for 2 hours. The conversion upon the termination of this reaction was 55%. There was observed neither solidification nor coloration of the reaction system throughout the reaction. Then, the polymerization product was treated in the same manner as in Example 1 to obtain colorless PTMG. The results of the analyses of this product and the catalytic efficiency α were as shown in Table 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][N:20]=[C:19]([OH:22])[CH:18]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(COC)OC>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][N:20]=[C:19]([OH:22])[CH:18]=4)=[CH:13][CH:12]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Oc1cc(-c2ccc(OCCc3cccc(Cl)n3)cc2)on1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Oc1cc(-c2ccc(OCCc3cccc(-c4ccc(F)cc4)n3)cc2)on1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-(2-(6-chloropyridin-2-yl)ethoxy)phenyl)isoxazol-3-ol (46.5 mg) in dimethoxyethane ethylene glycol dimethyl ether (3 ml), 18 mg of tetrakis triphenylphosphine palladium, 31 mg of 4-fluorophenylboronic acid and 0.2 ml of 2M aqueous sodium carbonate solution were added, and the reaction solution was stirred at 90° C. for 2 hours. The reaction solution was cooled, then diluted with a saturated saline solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified through reversed phase medium pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid). The solvent of the resultant fraction was diluted with ethyl acetate, washed with saturated sodium bicarbonate water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., methanol/chloroform (1:9)) to afford the title compound as a brown solid.
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=[C:13]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:12]=2)C=CC=CC=1>[Pd].C1COCC1.C(OCC)(=O)C>[CH2:29]([O:28][C:13]1[CH:12]=[C:11]([NH2:10])[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:14]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OCc2ccccc2)cc(OCCCOc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(OCCCOc2ccccc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.6 %

Procedure:
A mixture of 10.9 g of 3-(octadecyloxy)-5-(3-phenoxypropoxy)phenylcarbamic acid phenylmethyl ester and 1.2 g of 10% palladium on carbon in 200 ml of THF and 50 ml of ethyl acetate was stirred under a hydrogen atmosphere at room temperature for 17 hours. The catalyst was removed by filtration and the filtrate was concentrated to a solid which was recrystallized from ethyl acetate-hexane to give 8.0 g (92% yield, mp 74°-76°) of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzenamine. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[C:4](=[O:14])[C:3]=1[C:15]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:16]=1[C:17](O)=[O:18].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[OH:13][C:9]1[C:10]2[C:11](=[O:12])[C:2]3[O:1][C:17](=[O:18])[C:16]4[CH:20]=[C:21]([CH3:26])[CH:22]=[C:23]([O:24][CH3:25])[C:15]=4[C:3]=3[C:4](=[O:14])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(C)cc(C(=O)O)c1C1=C(O)C(=O)c2c(O)cccc2C1=O
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C)cc2c(=O)oc3c(c12)C(=O)c1cccc(O)c1C3=O
Temperature: 25 °C

Procedure:
The entire amount of the 2-(3,5-dihydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoic acid obtained above was dissolved in ethyl acetate (10 ml) and while the solution was stirred at room temperature, a mixture (1 ml:10 ml) of trifluoroacetic anhydride and acetic anhydride was added. The mixture was further stirred at the same temperature for an hour. This reaction mixture was washed with water and dilute aqueous sodium carbonate in that order, followed by drying over magnesium sulfate. The solvent was then distilled off and the residual brown oil was subjected to silica gel column chromatography to give vermillion-colored crystals (20 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:11][N:10]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].N12CCCN=C1CCCCC2>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:11]([S:36]([CH3:35])(=[O:38])=[O:37])[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)C(c1ccccc1)NN=C2Cc1c(Cl)cncc1Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(c1ccccc1)N(S(C)(=O)=O)N=C2Cc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
4-(3,5-Dichloro-pyridin-4-ylmethyl)-7-methoxy-1-phenyl-1,2-dihydrophthalazine (0.16 g, 0.4 mmole), prepared as described in example 111, in dry CH2Cl2 (10 ml), under N2, was added with triethylamine (0.1 ml, 0.72 mmole) and methanesulphonyl chloride (0.037 ml, 0.48 mmole). The mixture was stirred at room temperature overnight, then added again with triethylamine (0.05 ml, 0.36 mmole) and methanesulphonyl chloride (0.02 ml, 0.24 mmole). After 4 hours methanesulphonyl chloride (0.04 ml, 0.48 mmole) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.085 ml, 0.56 mmole) were added. After 24 hours the mixture was poured into water and the aqueous phase separated and extracted with CH2Cl2. The organic phase was washed in diluted citric acid, anhydrified and dried to give a solid which was flash chromatographed (eluent: petrolatum/ethyl acetate 7:3). The resultant solid was triturated in ethyl ether to give 0.21 g of the title compound (quantitative yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:13]([O:12][C:10]([NH:9][C:3]([CH3:8])([CH2:2][NH:1][S:28]([C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[Cl:20])(=[O:30])=[O:29])[C:4]([O:6][CH3:7])=[O:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C(C)(CN)NC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C)(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
0.103 g (0.341 mmol) of methyl 3-amino-2-benzyloxycarbonylamino-2-methylpropionate, 0.109 g (0.443 mmol) of 2,4 dichlorobenzenesulfonyl chloride and 0.237 ml (1.36 mmol) of DIEA are dissolved in 2 ml of DCM. The mixture is stirred at room temperature overnight. 2 ml are added to the reaction solution, and then the organic phase is separated off and dried over MgSO4, and the solvent is removed in vacuo. The crude product is purified by chromatography on 4 g of SiO2, EtOAc/DCM as eluent (gradient of 0-40%). 0.081 g of the desired product is obtained as an oil. MW=474 (calculated, monoisotopic), measured value: (M+H)+ 475.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][O:10][C:11]([C:13]1[CH:23]=[C:22]([OH:24])[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1)=[O:12].[N:25]1([C:29]([C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)=[O:30])[CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[CH3:9][O:10][C:11]([C:13]1[CH:23]=[C:22]([O:24][C:34]2[CH:33]=[CH:32][C:31]([C:29]([N:25]3[CH2:26][CH2:27][CH2:28]3)=[O:30])=[CH:36][CH:35]=2)[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1)=[O:12]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: O=C(c1ccc(Br)cc1)N1CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Temperature: 110 °C
Yield: 72.5 %

Procedure:
K3PO4 (1.23 g, 5.79 mmol), Pd(OAc)2 (41 mg, 0.81 mmol) and 2-di-t-butylphosphino-2′,4′6′-tri-i-propyl-1,1′-biphenyl (68 mg, 0.16 mmol) was added to a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (646 mg, 2.91 mmol) and azetidin-1-yl-(4-bromo-phenyl)-methanone (35a) (697 mg, 2.90 mmol) in toluene (10 mL). The reaction mixture was heated to 110° C. overnight. The mixture was filtered, washed with EtOAc, and concentrated. The residue was purified by flash column chromatograph eluting with 10-25% EtOAc in hexanes to give a white solid (802 mg, 72% yield). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=6.82 Hz, 2 H) 7.23 (s, 1 H) 7.20 (s, 1 H) 6.97 (d, J=7.33 Hz, 2 H) 4.24-4.34 (m, 4 H) 3.87 (s, 3 H) 2.88 (s, 2 H) 2.50-2.61 (m, 1 H) 2.32-2.42 (m, 1 H) 1.47 (s, 6 H); LCMS for C22H23NO5 m/z 382.00 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16])[CH2:30]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Reactant: Brc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Br)c4C3)c(F)c(NCCO)c2c1=O
Yield: 32.7 %

Procedure:
205 mg of 1-cyclopropyl-5-(2-hydroxyethylamino)-6,7,8- trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 131 mg of 4-bromoisoindoline, 182 mg of DBU, and 1.5 ml of are anhydrous DMF were processed in the same manner as in Example 20 to produce 102 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)[N:5]=[C:4]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:3]=1[N+:30]([O-])=O>N1C=CC=CC=1.[Pd]>[NH2:30][C:3]1[C:4]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:5][C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:7][C:2]=1[NH2:1]
Reactant: CCOC(=O)c1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N

Procedure:
130 mg (0.30 mmol) of the compound from example 62A were initially charged in pyridine (9 ml) and then 25 mg of palladium (10% on charcoal) were added. The mixture was hydrogenated under standard hydrogen pressure at RT overnight. The reaction mixture was then filtered through Celite and the filtercake was washed with methanol. The filtrate was concentrated, methanol was added to the residue, and the solids were filtered off. The filtrate was concentrated by rotary evaporation and the residue was dried under high vacuum. This gave 51 mg (83% purity, 36% of theory) of the title compound, which were converted without further purification.
Reaction SMILES: C(B(CC)OC)C.[Cl:8][CH2:9][CH:10]([OH:24])[CH2:11][C:12](=[O:23])[CH2:13][C:14]([N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[O:15].O1CCCC1.[BH4-].[Na+]>CO>[Cl:8][CH2:9][C@@H:10]([OH:24])[CH2:11][C@@H:12]([OH:23])[CH2:13][C:14]([N:16]([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:21])[CH3:22])=[O:15]
Reactant: CC(C)N(C(=O)CC(=O)CC(O)CCl)C(C)C
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(C(=O)C[C@H](O)C[C@H](O)CCl)C(C)C
Temperature: -72.5 °C
Reaction time: 0.42 h

Procedure:
Added 430 ml of diethyl methoxy borane to a cooled solution of 500 grams of (S) 6-chloro-5-hydroxy-N,N-diisopropyl-3-oxohexanamide, 3500 ml tetrahydrofuran and 1000 ml of methanol at −75 to −70° C. Stirred the reaction mixture at −75 to −70° C. for 25 minutes. Added 86.5 grains of sodium borohydride in lot wise. Stirred the reaction mixture for 2 hours at −75 to −70° C. Quenched the reaction mixture with hydrogen peroxide solution. Separated the organic and inorganic phases. Washed the organic layer with 10% sodium bicarbonate solution followed brine solution and water. Dried the organic layer over sodium sulphate. Distilled the solvent completely under reduced pressure to get the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C)C=O.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>O1CCCC1>[NH:18]1[C:17]([NH:16][C:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)=[O:10])=[N:21][N:20]=[N:19]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccnc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccnc(C(=O)Nc2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
A mixture of 1.06 g of 4-methyl-2-pyridinecarboxylic acid, 1.28 g of N,N'-carbonyldiimidazole, 25 ml of dimethylformamide and 12 ml of tetrahydrofuran is stirred at room temperature for 3 hours. 0.72 g of 5-aminotetrazole is added to the mixture and said mixture is stirred at 80° C. for 3 hours. Then, the reaction mixture is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is adjusted to pH 2 with 10% hydrochloric acid. The crystalline precipitates are collected by filtration, washed with water and then recrystallized from a mixture of dimethylformamide and water. 0.52 g of N-(5-tetrazolyl)-4-methyl-2-pyridinecarboxamide is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17]>>[Cl:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[C:16]([N:18]1[CH2:19][CH2:20][CH:21]([OH:24])[CH2:22][CH2:23]1)=[O:17]
Reactant: NC(Cc1cccc(Cl)c1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(NC(Cc1cccc(Cl)c1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-1-(4-hydroxy-piperidin-1-yl)-3-(3-chloro-phenyl)-propan-1-one. mp 98° C. dec.
Reaction SMILES: [CH2:1]([S:7](Cl)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1.Cl>CO>[CH2:1]([S:7]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:21][CH:22]=1)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N#CCC(=O)c1ccc(N)cc1
Reactant: CCCCCCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCCCCCS(=O)(=O)Nc1ccc(C(=O)CC#N)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 3.7 grams (0.02 Mol) hexane sulfonyl chloride, 3.2 grams (0.02 Mol) 4-aminobenzoylacetonitrile and 5 mL of pyridine was stirred at 0° C. for 1.5 hours. The resulting very thick brown solution was dissolved in 15 mL of methanol and dropwise added to 100 mL of 2N hydrochloric acid at 0° C. A tan precipitate formed which was stirred for 30 minutes, then filtered and washed with water and dried for 2 hours at 50° C./10 mm Hg to give 6.9 grams of crude product. This was recrystallized from aqueous ethanol to give 4.2 grams (13.6 mMol, 68% yield) of pure product, m.p.=125°-127° C.
Reaction SMILES: Cl.[CH3:2][CH:3]([NH:5][CH2:6][C:7]1([NH2:11])[CH2:10][NH:9][CH2:8]1)[CH3:4].[F:12][C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16](F)=[O:17]>C(=O)(O)[O-].[Na+].O1CCOCC1.O>[F:12][C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:15]([C:16]([N:9]2[CH2:10][C:7]([CH2:6][NH:5][CH:3]([CH3:4])[CH3:2])([NH2:11])[CH2:8]2)=[O:17])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(C)NCC1(N)CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)NCC1(N)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.6 %

Procedure:
To a mixture of the 3-{[(1-methylethyl)amino]methyl}azetidin-3-amine hydrochloride (20 mg, 0.079 mmol) in saturated sodium bicarbonate solution (1.0 mL) and dioxane (1.0 mL) was added 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (31 mg, 0.079 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined extract was washed with water then brine solution (5 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by reverse phase HPLC to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-amine (15 mg, 37% yield). 1H NMR (400 MHz, d4-Methanol): 7.46-7.43 (dd, 1H), 7.35-7.33 (dd, 1H), 7.31-7.27 (m, 1H), 7.08-7.01 (dd, 1H), 6.63, 6.58 (td, 1H), 4.09-4.07 (d, 1H), 3.91-3.85 (dd, 2H), 3.76-3.73 (d, 1H). 2.80-2.74 (m, 1H), 2.73 (s, 2H), 1.07-1.05 (d, 6H); MS (EI) for C20H22F3IN4O: 519 (MH+).