Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:47][C:48]1[S:49][CH:50]=[CH:51][N:52]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([NH:47][C:48]2[S:49][CH:50]=[CH:51][N:52]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1nccs1
Reactant: O=C(O)[C@H](CC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
A solution of 2(R)-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (80 mg, 0.26 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (177 mg, 0.40 mmol), and 2-aminothiazole (40 mg, 0.40 mmol) in methylene chloride (10 mL) at 25° C. was treated with triethylamine (0.11 mL, 0.79 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were sequentially washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 95/5 hexanes/ethyl acetate to 70/30 hexanes/ethyl acetate) afforded the 2(R)-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-N-thiazol-2-yl-propionamide (57 mg, 57%) as a white foam: EI-HRMS m/e calcd for C17H18Cl2N2O2S (M+) 384.066, found 384.1467.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:23]([N:25]1[CH2:29][CH2:28][S:27][CH2:26]1)=[O:24])=O)(C)(C)C.[H-].[Na+].CI.Cl.O1CCOC[CH2:36]1>CN(C=O)C.ClCCl>[CH3:36][N:14]([CH2:13][C@H:11]1[CH2:10][C@@H:9]([C:23]([N:25]2[CH2:29][CH2:28][S:27][CH2:26]2)=[O:24])[NH:8][CH2:12]1)[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2ccccc2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CI
Product: CN(C[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)C(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of (2S, 4R)-4-(benzoylamino-methyl)-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg, 0.43 mmol) in anhydrous DMF (8 mL) was added sodium hydride (13 mg, 0.56 mmol) under nitrogen. The mixture stirred for 15 minutes followed by the addition of methyl iodide (0.04 mL, 0.64 mmol). The mixture was allowed to stir for 2 hours at room temperature, concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (10 mL) and H2O (5 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide a yellow oil. To a solution of the oil in dichloromethane (10 mL) was added a solution of 4N HCl in dioxane (2 mL, 8 mmol) and the mixture was allowed to stir for 12 hours at room temperature. The mixture was concentrated under reduced pressure and the residue purified by RP-HPLC (CH3CN/H2O/TFA). MS (ESI) m/e 334 (M+H)+, 332 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 2.70 (m, 1H) 3.02 (s, 3H) 3.10 (m, 1H) 3.17 (t, 1H) 3.55 (m, 2H) 3.66 (m, 1H) 3.78 (m, 2H) 3.87 (m, 1H) 4.53 (m, 1H) 4.67 (m, 2H) 7.44 (dd, 2H) 7.48 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][CH3:11])[CH:4]=1)[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CC#N>[Br:19][C:8]1[CH:7]=[C:6]([F:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(F)c(OC)c1
Solvent: CC#N
Product: CCc1cc(OC)c(F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a solution of 4-ethyl-1-fluoro-2-methoxy-benzene (WO-2010/090537, 12.2 g, 79.1 mmol) in MeCN (150 mL) was added a solution of NBS (14.4 g, 80.7 mmol) in MeCN (50 mL). The resulting solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was diluted with diethyl ether (150 mL). Precipitated solid was removed by filtration and the filtrate was washed with sodium sulfite aqueous solution (100 mL) and brine (100 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow oil (18 g) in a 97% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[O:19][CH:18]=[N:17][CH:16]=3)[N:10]=2)[CH:3]=1.Br[CH:21]=[CH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.O(C(C)(C)C)[Li].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[C:11]([C:15]3[O:19][C:18]([CH:21]=[CH:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)=[N:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: N#Cc1ccc(C=CBr)cc1
Reactant: Cc1ccnc(Nc2cccc(-c3cnco3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]OC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccnc(Nc2cccc(-c3cnc(C=Cc4ccc(C#N)cc4)o3)n2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
A sealed tube was charged with a mixture of (4-methyl-pyridin-2-yl)-(6-oxazol-5-yl-pyridin-2-yl)-amine (200 mg, 0.793 mmol), 4-(2-bromovinyl)-benzonitrile (330 mg, 1.59 mmol), Pd(PPh3)4 (46 mg, 0.0396 mmol), LiOtBu (127 mg, 1.59 mmol) and anhydrous 1,4-dioxane (5 ml) and heated to 100° C. with stirring for 2 h. The cooled reaction mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2, eluting with 50% EtOAc in cyclohexane to afford the title compound as a yellow solid (76 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ=9.79 (s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 7.86-7.61 (m, 5H), 7.46 (d, J=16.3 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 6.78 (d, J=4.7 Hz, 1H), 2.35 (s, 3H). (ESI+) m/z 380 (M+H).
Reaction SMILES: Cl.[C:2]1([NH:12][NH2:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:20]1([NH:30][NH2:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(=O)C.[CH3:35][C@:36]12[C:42]([CH3:44])([CH3:43])[C@H:39]([CH2:40][CH2:41]1)[CH:38]([C:45](Cl)=[O:46])[C:37]2=O.N1C=CC=CC=1.Cl.O1CCOCC1>C1(C)C=CC=CC=1.ClCCCl.C(O)(=O)C.CO.ClCCl>[C:2]1([NH:12][NH2:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:35][C@@:36]12[C:42]([CH3:44])([CH3:43])[C@@H:39]([C:38]3[C:45](=[O:46])[N:30]([C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[NH:31][C:37]=31)[CH2:40][CH2:41]2
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: CC=O
Agent: Cl
Agent: NNc1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cccc4ccccc34)c(=O)c12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46 %

Procedure:
Naphthylhydrazine was prepared by treating a mixture of 1-naphthylhydrazine hydrochloride with 10% methanol/dichloromethane and saturated aqueous sodium carbonate). A solution of 1-naphthylhydrazine (501 mg, 3.2 mmol) in toluene (45 mL) was cooled to 0° C. under nitrogen, and a solution of acetaldehyde (440 μL, 7.9 mmol) in cole toluene (5 mL) was added dropwise over 15 min. The mixture was allowed to stir at 0° C. for 5 min and then at room temperature for 1 h. The solvent was decanted off and the remaining material was evaporated to give a dark oil which was dissolved in 1,2-dichloroethane (5 mL). The solution was added to a solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; ˜1 equivalent) and pyridine (˜1.5 equivalents) in 1,2-dichloroethane (10 mL) at 0° C. to give an immediate precipitate. The reaction mixture was stirred at room temperature for 15 min, then at 50° C. for 40 min. The reaction mixture was cooled to room temperature and HCl in dioxane (4 M; 3 mL, 12 mmol) was added. The mixture was stirred at room temperature for 5 min, then glacial acetic acid (10 mL) was added and the mixture was stirred at 100° C. for 25 min. The reaction mixture was cooled, and solvents were evaporated. Dichloromethane (200 mL) was added and the solution was washed with 1:1 water/brine (2×50 mL). The combined aqueous layers were back-extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL), dried (magnesium sulfate), filtered, evaporated and purified by elution through silica gel with 30% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and dried under high vacuum for 20 min to give (4S,7R)-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (459 mg, 46%) as an orange gummy solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH:25][C:26](=[O:28])[CH3:27])[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)=[O:6].[CH3:29]I>>[C:26]([N:25]([C:24]1[CH:23]=[CH:22][C:4]([C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH2:9][CH2:8]2)=[O:6])=[CH:3][C:2]=1[CH3:1])[CH3:29])(=[O:28])[CH3:27]
Reactant: CI
Reactant: CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1C
Product: CC(=O)N(C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1C

Procedure:
In a manner analogous to that described in Example 5, 5 g of 1-[3-methyl-4-(N-acetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine are methylated with 0.8 g of methyl iodide to form 1-[4-(N-acetyl-N-methylamino)-3-methylbenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine and converted into the hydrochloride having a melting point of 195°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:36])[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=1)[CH3:6]>>[CH2:5]([O:7][C:8](=[O:36])[C:9]1[C:14]([NH:15][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=[C:11]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=2[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:10]=1)[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc(C2=C(c3cc(C)ccc3OCc3ccccc3)CCC2)ccc1N
Product: CCOC(=O)c1cc(C2=C(c3cc(C)ccc3OCc3ccccc3)CCC2)ccc1NC(C)=O

Procedure:
Prepared by general procedure E but using acetyl chloride instead of propionyl chloride and 3-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic acid ethyl ester instead of 5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[N:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[N:10]=[C:11]([S:14][CH3:15])[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:24])=[O:5])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:32])C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[N:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[N:10]=[C:11]([S:14]([CH3:15])=[O:32])[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c2cnc(SC)nc2n(C2CCCC2)c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C)c2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
8-cyclopentyl-5-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (138 mg, 0.40 mmol) was dissolved in CH2Cl2 (6 mL) and 2-benzenesulfonyl-3-phenyl-oxaziridine (155 mg, 0.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then the solvent was removed under reduced pressure and the remaining residue was purified by prepative TLC (50% ethyl acetate/hexane). The more polar, product-containing, reaction was extracted into CH2Cl2 and the solvent evaporated to provide 8-cyclopentyl-2-methanesulfinyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a white solid (110 mg, 75.7%). M++1: Calc'd. 364.4, Found 364.2.
Reaction SMILES: ClC1C=CC(C(C2C=CC(C=O)=CC=2)N2CC(=CS(CC3C=C(F)C=C(F)C=3)(=O)=O)C2)=CC=1.Cl.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:60]2[CH:65]=[CH:64][C:63]([CH:66]3OCC[O:67]3)=[CH:62][CH:61]=2)[N:43]2[CH2:46][C:45](=[C:47]([C:52]3[CH:57]=[C:56]([F:58])[CH:55]=[C:54]([F:59])[CH:53]=3)[S:48]([CH3:51])(=[O:50])=[O:49])[CH2:44]2)=[CH:38][CH:37]=1.[OH-].[Na+]>O1CCCC1.O.ClCCl>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:60]2[CH:61]=[CH:62][C:63]([CH:66]=[O:67])=[CH:64][CH:65]=2)[N:43]2[CH2:44][C:45](=[C:47]([C:52]3[CH:53]=[C:54]([F:59])[CH:55]=[C:56]([F:58])[CH:57]=3)[S:48]([CH3:51])(=[O:50])=[O:49])[CH2:46]2)=[CH:38][CH:37]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(C3OCCO3)cc2)C1)c1cc(F)cc(F)c1
Agent: Cl
Agent: O=Cc1ccc(C(c2ccc(Cl)cc2)N2CC(=CS(=O)(=O)Cc3cc(F)cc(F)c3)C2)cc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(C=O)cc2)C1)c1cc(F)cc(F)c1
Reaction time: 20 h
Yield: 105.1 %

Procedure:
(−)-1-[(4-Chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidine may be prepared in the following manner: 3.32 cm3 of a 5 N solution of hydrochloric acid are poured into a solution of 0.83 g of (+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine in 5 cm3 of tetrahydrofuran and then the mixture is kept stirring for 20 hours. Dichloromethane and water are added to the reaction medium followed by a 30% aqueous solution of sodium hydroxide until a pH=14 is obtained. The aqueous phase is extracted with dichloromethane, the organic phase is washed successively with water, with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kpa). 0.8 g of (−)-1-[(4-chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[CH:12][N:11]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1ncc(F)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Hydroxy-acetic acid methyl ester (0.96 g, 10.7 mmol) was dissolved in 2 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (0.42 g, 10.7 mmol) was added thereto at room temperature. After stirring for 30 minutes, 2-chloro-5-fluoro-3-nitro-pyridine (1.57 g, 8.89 mmol) dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain (5-fluoro-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow liquid (1.35 g, 66%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1.CN(C)C=O>[CH2:14]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(O)cccc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(OCc2ccccc2)cccc1C(=O)O
Temperature: 0 °C
Yield: 72.5 %

Procedure:
To a solution of 3-hydroxy-2-methyl-benzoic acid (55, 5.0 g, 0.033 mol) in tetrahydrofuran (100 mL) and N,N-dimethylformamide (50 mL), sodium hydride (4.4 g as 60% dispersion in mineral oil, 0.11 mol) was added slowly over 30 minutes and the reaction was stirred at 0° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature, then stirred at room temperature for 1 hour. Benzyl bromide (9.0 mL, 0.076 mol) was added slowly into the reaction mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, washed with a solution of ammonium chloride and ammonium hydroxide (4:1), brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (56, 5.8 g, 73%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[NH:11][C:12]([C:14]1[NH:18][C:17]2[C:19]([Cl:23])=[C:20]([Cl:22])[S:21][C:16]=2[CH:15]=1)=[O:13].C(N(CC)CC)C.[Cl:31][CH2:32][C:33](Cl)=[O:34].O>ClCCl>[Cl:22][C:20]1[S:21][C:16]2[CH:15]=[C:14]([C:12]([NH:11][C@@H:3]3[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@H:2]3[NH:1][C:33](=[O:34])[CH2:32][Cl:31])=[O:13])[NH:18][C:17]=2[C:19]=1[Cl:23]
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
N-[(1R,2R)-1-Amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 8, 602 mg, 1.6 mmol) was dissolved in dichloromethane (30 mL), to this was added triethylamine (0.25 mL, 1.8 mmol) and chloroacetyl chloride (0.14 mL, 1.8 mmol). The solution was stirred at ambient temperature for 16 hours, after which triethylamine (0.25 ml, 1.8 mmol) and chloroacetyl chloride (0.14 ml, 1.8 mmol) were added before stirring for 1 hour. To the resulting slurry, water (15 mL) was added before filtering to give the title product (532 mg, 73%) as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C=O)C>[O:11]=[C:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[NH:1][CH2:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[NH:6]1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: Nc1cccc2c1CC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C1Cc2c(NCC(=O)OCc3ccccc3)cccc2N1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 4-amino-1,3-dihydro-2H-indol-2-one (300 mg, 2.03 mmol), benzyl bromoacetate (0.32 mL, 2.03 mmol), cesium carbonate (660 mg, 2.03 mmol), and potassium iodide (336 mg, 2.03 mmol) in DMF (10 mL) was stirred at 50° C. for 4 h. The cooled reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=297 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[N:15][OH:16]
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CCO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)C(=NO)CCO2
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
5.2 g (29.2 mmol) of 6-methoxychroman-4-one were dissolved in ethanol and 2.53 g (36.5 mmol) hydroxylamine hydrochloride and 2.99 g (36.5 mmol) sodium acetate dissolved in 10 ml of water were added. The mixture was stirred at 65° C. for 1.5 hours. The mixture was allowed to cool to room temperature and concentrated. The residue was dissolved in methyl-tert-butylether. The organic phase was washed with water, dried over MgSO4 and concentrated to give 5.6 g (29.4 mmol, quant.) of crude product, which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42]>CN(C=O)C.[Cu](I)I.O>[F:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[CH2:35][CH2:34][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[C:5]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11][C:6]1=2
Reactant: Fc1ccccc1CCBr
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2c(n(CCc3ccccc3F)c3ccc(Cl)cc23)CC1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by following general procedure 4. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1.0 mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol) and then 1-(2-bromoethyl)-2-fluorobenzene (203 mg, 1 mmol) in DMF. The reaction mixture was stirred at 90° C. under argon atmosphere for 12 h and monitored by LCMS. After completion of the reaction, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel 100-200 mesh) (gradient 5% MeOH:DCM). The pure product was converted to its oxalate salt using oxalic acid and THF.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])[N:5]=[CH:4][C:3]=1[CH:15]=O.NC1N(C2C=CC=CC=2Cl)N=CC=1C=O.C(O)C.[C:35](OCC)(=[O:42])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].N1CCCCC1>>[F:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([F:14])[C:7]=1[N:6]1[C:2]2[NH:1][C:35](=[O:42])[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:15][C:3]=2[CH:4]=[N:5]1
Reactant: Nc1c(C=O)cnn1-c1c(F)cccc1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: Nc1c(C=O)cnn1-c1ccccc1Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cnn(-c3c(F)cccc3F)c2[nH]c1=O
Temperature: 75 °C
Yield: 100 %

Procedure:
In a 500 mL round-bottomed flask was added 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbaldehyde (7.77 g, 35 mmol; prepared in a fashion similar to that described for 5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbaldehyde in Example 1 above) followed by ethanol (100 ml, 35 mmol). To the solution was added diethyl malonate (11 ml, 70 mmol) and piperidine (3.4 ml, 35 mmol) and the mixture was heated to 75° C. overnight. The reaction mixture was concentrated under reduced pressure and the brown residue was treated with 200 mL of a 1:1 solution of EtOAc:Hexanes. The precipitated solid was then filtered through a sintered glass frit and rinsed with hexanes. It was dried under high vacuum to afford the title compound (11.13 g, 100% yield) as a beige crystalline solid. MS (ESI, pos.ion) m/z: 306.0 (M+1).