Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH:11]=1)[CH2:3][C:4](O)=[O:5].CN1CCOCC1.ClC(OCC)=O.B.[Li]>O1CCCC1.O>[OH:1][CH:2]([CH2:3][CH2:4][OH:5])[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:22][CH:21]=2)[CH:11]=1
Reactant: COc1ccc(C(=O)NCC(O)CC(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Agent: B
Agent: CCOC(=O)Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: COc1ccc(C(=O)NCC(O)CCO)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
The obtained 3-hydroxy-4-{4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoylamino}butyric acid (27 mg) and 15 μL of N-methylmorpholine were dissolved in 3 mL of tetrahydrofuran under an atmosphere of nitrogen, and the solution was cooled to −15° C. Ethyl chloroformate (13 μL) was added to the solution, the mixture was stirred for 15 minutes, and then 18.4 mg of lithium boron hydride was added. After the mixture was stirred for 30 minutes at −15° C., 1 mL of water was added, and the reaction was quenched. The reaction mixture was purified by preparative high-performance liquid chromatography to obtain 21 mg (78%) of N-(2,4-dihydroxybutyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzamide.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].CSC.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=1.[CH:22]1([Mg]Br)[CH2:24][CH2:23]1>O1CCCC1.[Cu](I)I>[Br:14][C:15]1[CH:20]([CH:22]2[CH2:24][CH2:23]2)[C:19]([F:21])=[CH:18][N:17]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Fc1cncc(Br)c1
Reactant: Br[Mg]C1CC1
Agent: I[Cu]I
Solvent: CSC
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)N1C=C(F)C(C2CC2)C(Br)=C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Phenyl chloroformate (0.764 mL, 0.0060 mol) was added to a mixture of copper iodide (1.082 g, 0.0056 mol), dimethylsulphide (2.78 mL, 0.0380 mol) and 3-bromo-5-fluoropyridine (1.0 g, 0.0056 mol) in anhydrous tetrahydofuran (25 mL) at room temperature and the mixture was stirred for 40-50 min. To this suspension cyclopropyl magnesium bromide (12.13 mL, 0.0060 mol, 0.5M solution in tetrahydofuran) was added at −25 to −20° C. over 30-40 min. The mixture was stirred at this temperature for 30 min, and then warmed slowly to room temperature over 1.0-1.5 h. The reaction mixture was quenched with 20% ammonium chloride (25 mL), followed by extraction of the aqueous layer with ethyl acetate (50 mL). The organic layer was washed with 20% ammonium chloride (25 mL), then saturated sodium chloride (25 mL), and dried over anhydrous sodium sulphate. Silica gel chromatography using 0-5% ethyl acetate-hexane gradient yielded crude phenyl 3-bromo-4-cyclopropyl-5-fluoropyridine-1 (4H)-carboxylate MS (M+1): 339.7.
Reaction SMILES: Cl.C[O:3]C(=O)[C@H](CCC(OC)=O)N.COC(=O)[C@H](CCC(OC)=O)NN[C:20](=[O:38])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:23][C:22]=1[N+:35]([O-:37])=[O:36]>>[C:31]([O:30][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([OH:38])=[O:3])=[C:22]([N+:35]([O-:37])=[O:36])[CH:23]=1)=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: COC(=O)CC[C@H](NNC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: Cl
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1

Procedure:
The synthesis was achieved in analogy to example 2 by using L-glutamic acid-dimethylester-hydrochloride instead of the L-glutamic acid-di-tert.-butylester-hydrochloride. From 14.8 g of 4-(tert-butoxycarbonylamino)-2-nitrobenzoic acid 27.4 g of crude dimethyl-N-(4-(tert.-butoxycarbonylamino)-2-nitrobenzamido)-L-glutamate were obtained which were purified twice by flash chromatography using silicagel 60 and ethylacetate/n-heptane/65:35 as eluent. After purification 17.38 g of dimethyl-N-(4-(tert.-butoxycarbonylamino)-2-nitrobenzamido)-L-glutamate were obtained.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][C:24]1=O>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:30][CH2:31][C:32]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:28]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C1CCc2ccccc2C1
Product: CCCC(NC1CCc2ccccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 3,4-Dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 24.3, 26.6, 28.0, 28.3, 29.5, 30.5, 36.5, 36.6, 36.7, 37.5, 53.3, 53.6, 56.0, 59.1, 60.4, 60.8, 67.3, 104.7, 126.0, 126.1, 126.2, 128.8, 128.9, 129.5, 129.6, 131.1, 134.8, 135.3, 135.9, 136.3, 137.3, 172.6; MS m/z 438.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.C[Si]([C:14]#[N:15])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:14]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][N:6]=1)#[N:15]
Reactant: COc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccnc(C#N)c1
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Commercially available 4-methoxypyridine N-oxide (50 g, 0.4 mol) was dissolved in dichloromethane (200 mL), and to it was added trimethylsilylcyanide (67.4 mL, 0.506 mol) at room temperature. Dimethylcarbamyl chloride (46.5 mL, 0.506 mol) was added dropwise with stirring to the reaction mixture over a 30-min period. The reaction mixture was stirred at room temperature for 24 hours. A solution of 10% aqueous potassium Carbonate (100 mL) was added dropwise, and stirring was continued for 15 minutes. The organic layer was separated, dried, and concentrated to afford 2-cyano-4-methoxypyridine 1 (51.5 g, 96%) as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[OH:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19].C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:16]([OH:15])[CH:17]=1
Reactant: Cc1ccc(N)cc1O
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1O
Yield: 89.4 %

Procedure:
To 1.5 g of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 40 mL of absolute ethanol was added 1.1 g of 3-hydroxy-4-methylaniline. After stirring the reaction under an inert atmosphere for 16 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/ether/hexanes. Drying in vacuo yielded 1.9 g (90%) of 6-fluoro-4-(3-hydroxy-4-methyl-phenylamino)-[1,7]naphthyridine-3-carbonitrile as a yellow powder: melting point 236-239° C. (decomposed); mass spectrum (m/e): M+H 294.9.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([O:13][CH2:14][CH:15]1OC1)(=[O:12])[C:9](C)=C>>[CH2:1]=[CH2:2].[C:8]([O:13][CH:14]=[CH2:15])(=[O:12])[CH3:9].[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: C=C(C)C(=O)OCC1CO1
Agent: O=C1C=CC(=O)O1
Product: C=C
Product: C=COC(C)=O

Procedure:
the above two copolymers in which the maleic anhydride is replaced by glycidyl methacrylate,
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28](C2C=CC=CC=2)=CS[C:25]=1[C:35](OC)=O.C(OCC)(OCC)OCC.[C@@H]1(N)C2C(=CC=CC=2)CCC1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C@@H:1]4[C:6]5[C:5](=[CH:28][CH:24]=[CH:25][CH:35]=5)[CH2:4][CH2:3][CH2:2]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: N[C@H]1CCCc2ccccc21
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1[C@H]1CCCc2ccccc21
Yield: 53.3 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), (S)-1,2,3,4-tetrahydronaphthalen-1-amine (0.141 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 82.1 mg (0.23 mmol, 53.3% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([NH:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])=[O:18]>CS(C)=O.O>[CH3:16][C:17]([NH:19][C:20]1[CH:25]=[C:24]([O:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])=[O:18]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,4-dichlorophenol (1.2 g, 7.6 mmol) and potassium carbonate (2.1 g, 15.2 mmol) is stirred together in dimethylsulfoxide (20 ml). N-methylcarbonyl 2-nitro-5-fluoroaniline (1.5 g, 7.6 mmol) is added in portions. After 1 hour, the reaction is heated to 100° for 1.5 hours. The reaction is then cooled to RT and diluted with water. A solid is collected, dissolved in chloroform, washed with water, dried and stripped to give N-methylcarbonyl 2-nitro-5-(2,4-dichlorophenoxy)aniline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.O.[OH-].[Na+]>CS(C)=O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Nc2cncc(C(=O)Nc3nnn[nH]3)n2)cc1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 15 ml of dimethylsulfoxide, 5.36 g of p-toluidine was added, and the mixture was heated for 18 hours at 80°-90 ° C., and heated for 6 hours at 100°-110 ° C. Water and 10%-sodium hydroxide aqueous solution was added to the reaction mixture, and the aqueous alkaline solution was washed with chloroform. Aqueous layer was filtered, and the filtrate was adjusted with 10%-hydrochloric acid to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.93 g of the desired compound as yellow needles, m.p. 289.5°-294 ° C. (decomp.).
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][CH:8]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][CH:2]([CH3:6])[C:3]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH:8]1[CH3:7])=[O:4]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(Cl)C(=O)N1c2ccccc2OCC1C
Reaction time: 0.5 h
Yield: 165.2 %

Procedure:
5.35 ml (55 mmoles) of 2-chloropropionyl chloride are added dropwise, at a temperature of 20° to 25° C. and while stirring, to a suspension of 7.5 g (50 mmoles) of 2,3-dihydro-3-methyl-1,4-benzoxazine and 5.8 g (55 mmoles) of sodium carbonate in 120 ml of benzene. The reaction mixture is then stirred at the same temperature for 30 minutes and is then taken up in a mixture of water and ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystallising the residue from diisopropyl ether gives 19.8 g of 4-(2-chloropropionyl)-2,3-dihydro-3-methyl-1,4-benzoxazine, melting point 88°-90° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:28][OH:29]>>[F:27][C:5]1[N:6]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[C:3]([CH2:2][O:29][CH3:28])[N:4]=1
Reactant: CO
Reactant: Fc1nc(CCl)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 1 h

Procedure:
4-Chloromethyl-2-fluoro-1-triphenylmethylimidazole was dissolved in MeOH, and allowed to stand 1 hour, giving 2-fluoro-4-methoxymethyl-1-triphenylmethylimidazole. This was reacted at 60° for 3 hours in CHCl3 /MeOH solution with t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate in the presence of toluene-p-sulphonic acid, and the product purified by chromatography to give t-butyl 3-acetoxymethyl-7-(4-methoxymethylimidazol-2-yl)aminoceph-3-em-4-carboxylate, having the following n.m.r. spectrum in d6DMSO: 1.5 (s, 9H); 2.05 (s, 3H); 3.3 (s, 3H); 3.5 (d, 1H); 3.7 (d, 1H); 4.3 (s, 2H); 4.7 (d, 1H); 5.0 (d, 1H); 5.2 (d, 1H); 5.7 (d, 1H); 7.1 (s, 1H).
Reaction SMILES: CN([C:4]([O:8]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([C:27]1[S:28][CH:29]=[C:30]([C:32]([N:34]2[CH2:39][C:38]3([CH2:44][CH2:43][N:42]([CH2:45][CH2:46][C:47]4[CH:60]=[CH:59][C:50]([CH2:51][CH2:52][O:53][CH2:54][CH2:55]C(O)=O)=[CH:49][CH:48]=4)[CH2:41][CH2:40]3)[O:37][CH2:36][CH2:35]2)=[O:33])[N:31]=1)[CH3:26].[CH3:61][O:62][CH:63]([O:69][CH3:70])[CH2:64][NH:65][CH2:66][CH2:67][CH3:68].C(N(CC)CC)C>ClCCl>[CH3:61][O:62][CH:63]([O:69][CH3:70])[CH2:64][N:65]([CH2:66][CH2:67][CH3:68])[C:4](=[O:8])[CH2:55][CH2:54][O:53][CH2:52][CH2:51][C:50]1[CH:49]=[CH:48][C:47]([CH2:46][CH2:45][N:42]2[CH2:41][CH2:40][C:38]3([O:37][CH2:36][CH2:35][N:34]([C:32]([C:30]4[N:31]=[C:27]([CH2:25][CH3:26])[S:28][CH:29]=4)=[O:33])[CH2:39]3)[CH2:44][CH2:43]2)=[CH:60][CH:59]=1
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)O)cc4)CC3)C2)cs1
Reactant: CCCNCC(OC)OC
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC(OC)OC)C(=O)CCOCCc1ccc(CCN2CCC3(CC2)CN(C(=O)c2csc(CC)n2)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.33 g) was added to a solution of 3-(4-(2-(4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoic acid [Example 3, step e] (0.50 g), N-(2,2-dimethoxyethyl)propan-1-amine [Liebigs Annalen der Chemie 1979, 11, 1818] (0.12 g) and triethylamine (0.56 mL) in dichloromethane (5 mL) at 0° C. under nitrogen, and the mixture stirred at ambient temperature for 2 hours. The mixture was washed with water, the organic phase was separated, dried, filtered and concentrated in vacuo to afford the subtitled compound as an orange oil. Yield 0.43 g.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:17].[CH3:18]O>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:18])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:17]
Reactant: CO
Reactant: COC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Product: CCOC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1

Procedure:
Synthesized in an analogous fashion as methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate, but MeOH from step 1 was removed and EtOH was used for step 2. MS (ESI) m/z: Calculated: 315.0; Observed: 316.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13](C)[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.8 g of 6-chloro-1-(2-chlorophenyl)-1'-methyl-spiro[indoline-3,4'-piperidine], free base of Example 28, and 0.5 g of phenyl chloroformate in 20 ml of methylene chloride is stirred at ambient temperature for 16 hours. Thereafter, the mixture is successively washed with 10% sodium hydroxide, washed with water, dried and concentrated under vacuum leaving a brownish oil. The oil is passed through an alumina column, ether eluant, providing a colorless gum of 6-chloro-1-(2-chlorophenyl)-1'-phenoxycarbonylspiro[indoline-3,4'-piperidine]. IR and NMR spectra confirm the assigned structure.
Reaction SMILES: [C:1]([C@@H:4]([C@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[NH2:11][C@@H]1C[C@H](C(OC)=O)C=C1.[Cl-].[NH4+:22].N.CO>C(O)C>[NH4+:11].[NH4+:22].[C:8]([O-:10])(=[O:9])[CH:6]([CH:4]([C:1]([O-:3])=[O:2])[OH:5])[OH:7]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: COC(=O)[C@@H]1C=C[C@H](N)C1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 2 h

Procedure:
To a mixture of (1S,4R)-Methyl 4-aminocyclopent-2-ene-1-carboxylate L-tartrate (10 g, 34.3 mmol) and ammonium chloride (1.85 g, 34.3 mmol) in ethanol (79 g) was added a 2M solution of ammonia in methanol (17.2 mL, 34.4 mmol). The mixture was stirred for 2 h, resulting in precipitation of the tartaric acid di-ammonium salt. The solid was removed by filtration and the filtrate was concentrated to about 10 mL. The concentrated filtrate was diluted with methyl isobutyl ketone (MIK), resulting in precipitation of (1S,4R) Methyl-4-aminocyclopent-2-ene-1-carboxylate hydrochloride. The solid was collected by filtration and dried in a vacuum oven (100 mbar) at 50° C. for 24 h.
Reaction SMILES: [NH2:1][C@H:2]([CH2:4][OH:5])[CH3:3].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C.O1CCCC1>[CH2:6]([O:13][C:14]([NH:1][C@@H:2]([CH3:3])[CH2:4][OH:5])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@@H](CO)NC(=O)OCc1ccccc1

Procedure:
A procedure similar to that described in Preparation 7 was repeated, except that 14.55 g of L-alaninol, 126 ml of a 30-35% w/v solution of benzyloxycarbonyl chloride in toluene, 29.6 ml of triethylamine and 100 ml of anhydrous tetrahydrofuran were used, to give 8.15 g of the title compound, melting at 79° C. to 80° C.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1.[S:22]1[CH:26]=[CH:25][C:24](B(OC(C)C)OC(C)C)=[CH:23]1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: CC(C)OB(OC(C)C)c1ccsc1
Reactant: Fc1ccc(Nc2ncnc3ccc(Br)cc23)cc1Cl
Agent: Cl
Product: Fc1ccc(Nc2ncnc3ccc(-c4ccsc4)cc23)cc1Cl
Yield: 51 %

Procedure:
Using an analogous procedure to that described in Example 5 except that the reaction mixture was heated to reflux for 2 hours, 6-bromo4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 3-thienylboronate to give 4-(3-chloro-4-fluoroanilino)-6-(3-thienyl)quinazoline in 51% yield, m.p. 195-197° C.; NMR Spectrum: 7.5 (t, 1H), 7.7-7.9 (m, 4H), 8.05 (m, 1H), 8.2 (m, 1H), 8.25 (m, 1H), 8.6 (s, 1H), 8.8 (d, 1H), 9.9 (broad s, 1H); Elemental Analysis: Found C, 57.8; H, 3.3; N, 10.6; C18H11ClFN3S 1.15H2O requires C, 57.4; H, 3.6; N, 11.2%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].[OH2:18].C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:18])[CH:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: OC1CN(Cc2ccccc2)CC1O
Yield: 90 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at 40° C. without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 17.4 g of 1-benzyl-3,4-dihydroxypyrrolidine (yield 90.0%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6]OCC[C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[O:16]1[CH2:21][CH2:20]C(CC=O)[CH2:18][CH2:17]1.[S].C(CC(OCC)=O)#N>>[NH2:1][C:2]1[S:10][C:5]([CH:6]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(N)sc2c1CCOC2
Reactant: O=CCC1CCOCC1
Agent: [S]
Solvent: CCOC(=O)CC#N
Product: CCOC(=O)c1cc(C2CCOCC2)sc1N

Procedure:
Prepared by proceeding in a similar manner to Intermediate 7, starting from (tetrahydropyran-4-yl)acetaldehyde, sulphur and ethyl cyanoacetate
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[CH3:35]O>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([O:18][CH3:35])=[O:17])=[O:7])=[CH:30][CH:31]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CO
Reactant: O=C(O)c1ccc(-c2ccccc2Cl)cc1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3Cl)cc2)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-chloro[1,1′-biphenyl]-4-carboxylic acid, and methanol, the title compound isolated as a mixture of two isomers in 92.3% purity by HPLC.
Reaction SMILES: [N:1]([C:4]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([CH3:21])[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8]2[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>CCO.O.[Zn]>[CH3:20][N:17]1[CH2:18][CH2:19][C:7]2[N:6]([CH2:5][C:4]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([NH2:1])[CH3:21])[C:14]3[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=3[C:8]=2[CH2:16]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(N=[N+]=[N-])c2cccnc2)CCN(C)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(N)c2cccnc2)CCN(C)C1
Temperature: 80 °C
Yield: 0.4 %

Procedure:
5-(2-Azido-2-(pyridin-3-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Crude) (500 mg, 1.4 mmol) was dissolved in EtOH (4 mL) and water (1 mL). Ammonium chloride (243 mg, 4.5 mmol) followed by zinc dust (293 mg, 4.5 mmol) were added to the reaction mixture and heated at 80° C. for 1 h. The reaction mixture was concentrated to dryness, basified with aqueous ammonia solution and extracted with EtOAc (150 mL). The organic layer was dried over sodium sulfate, evaporated in vacuo and purified by reverse phase HPLC to afford 2 mg of 1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-amine. 1H NMR (CD3OD, freebase): δ (ppm): 8.39 s (1H), 8.3 d (1H), 7.72 d (1H), 7.32 t(1H), 7.11 (1H), 6.91 d (1H), 6.8 d (1H), 4.18 dd (2H), 3.61 dd (2H), 2.7 m (2H), 2.46 s (3H), 2.35 s (3H),2.26 m (2H). Chiral HPLC provided enantiomers 149a and 149b.