Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH:24]([C:27]1[N:31]=[C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[O:29][N:28]=1)([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1>[CH:24]([C:27]1[N:31]=[C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][N:34]([C:2]3[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:3]=3)[CH2:33]2)[O:29][N:28]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1noc(C2CCCNC2)n1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(c3nc(C(C)C)no3)C2)nc1-c1ccc(C)cc1
Yield: 18.6 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 3-isopropyl-5-(piperidin-3-yl)-1,2,4-oxadiazole (0.167 g; 0.856 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.026 g (18%) of the titled compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH:22]2[O:24][CH2:23]2)=[CH:17][CH:16]=1>C1COCC1.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])([CH:22]2[CH2:23][O:24]2)[OH:25])=[CH:17][CH:16]=1
Reactant: Fc1ccccc1Br
Reactant: O=C(c1ccc(Cl)cc1)C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)(c1ccccc1F)C1CO1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution of 0.9 g of 2-bromofluorobenzene in 10 mL of THF and 20 mL of diethyl ether was added 3.2 mL of a 1.6M solution of n-butyllithium in hexanes at -78°. After the addition was complete, a solution of 0.9 g of 4'-chloro-2,3-epoxypropiophenone (J.T. Lumb, Tetrahedron Lett., 1970, 579) in 5 mL of ether was added, and the reaction mixture was allowed to warm to room temperature. After being quenched with 10 mL of saturated NH4Cl (aqueous), the mixture was separated, the organic phase was washed with brine, dried (MgSO4), filtered, concentrated, and triturated with hexanes to afford 1.0 g of the title compound, m.p. 120°-122°.
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][C@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:14][C@H:15]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N[C@H]1c2ccccc2C[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
5-Chloroindole-2-carboxylic acid (2.8 g, 14 mmol), tert-Butyl [(1S,2S)-2-amino-2,3-dihydro-1H-inden-1-yl]carbamate (3.47 g, 14 mmol), DIPEA (4.9 ml, 28 mmol) and HOBT (1.89 g, 14 mmol) were dissolved in DCM (100 mL), stirred for 5 mins, then EDCI (3.2 g, 16.7 mmol) was added and the reaction stirred for 3 hours. The volatiles were removed by evaporation under reduced pressure, EtOAc (125 mL) was added and the organic solution washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (5.7 g, 93%) as a pale brown foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Fc1cccc(Oc2cncc(Cl)n2)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1cc(Nc2cncc(Oc3cccc(F)c3)n2)cc(OC)c1OC
Yield: 61 %

Procedure:
Using Method EE with 2-chloro-6-(3-fluorophenyloxy)-pyrazine (200 mg, 0.89 mmol) and 3,4,5-trimethoxyaniline (196 mg, 1.07 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (200 mg). Yield: 61%. 1H NMR (250 MHz, DMSO-d6) δ 3.44 (s, 6H, [CH3O]3+5), 3.55 (s, 3H, [CH3O]4), 6.77 (s, 2H, Harom 2′+6′), 7.02-7.09 (m, 2H, Harom 4+6), 7.16 (d, 1H, Harom 2, JF=8.8 Hz), 7.43 (q, 1H, Harom 5, J=8.5 Hz), 7.78 (s, 1H, HPz 5), 7.98 (s, 1H, HPz 3), 9.61 (s, 1H, NH). m/z: 372.1 [(M+H)+, calcd for C19H18FN3O4 371.1].
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:29][C:28]1[C:23]([N:17]2[CH2:18][CH2:19][C:11]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=4)=[N:15][CH:14]=[N:13][C:12]=3[CH2:16]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Fc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccnc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cc2)C1
Temperature: 170 °C

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.15 g, 0.51 mmol), 2-chloro-3-fluoropyridine (0.134 g, 0.10 mmol), N,N-diisopropylethylamine (0.133 mL, 0.76 mmol) and heating the reaction mixture 9 h at 170° C. to obtain 0.062 g of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:43])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:43])([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(F)CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester, from Example 511, (80 mg, 0.16 mmol) in DCM (8 mL) at −78° C. was added DAST (200 μL, 1.52 mmol). The reaction mixture was stirred at −78° C. for 30 min then allowed to warm to RT and stirred for 16 h. The reaction mixture was stirred at RT for 16 h then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM (3×5 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in DCM) to give 4-Fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (45 mg, 56%). LCMS: RT=5.05 min, [M+H]+=514
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([O:20][C:21](=[O:26])[CH2:22][CH2:23][C:24]#[CH:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[CH2:13]([O:20][C:21](=[O:26])[CH2:22][CH2:23][C:24]#[C:25][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CCCC(=O)OCc1ccccc1
Reactant: FC(F)(F)Oc1cccc(I)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CCC#Cc1cccc(OC(F)(F)F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a degassed (Ar) solution of 1-iodo-3-trifluoromethoxy-benzene (0.54 ml, 3 mmol) in acetonitrile (30 ml) was added pent-4-ynoic acid benzyl ester (719 mg, 4 mmol; A. Rosowsky, R. A. Forsch, F. S. Queener, J. Med. Chem. 2003, 46, 1726-1736), PdCl2(Ph3P)2 (122 mg, 0.17 mmol), cuprous iodide (33 mg, 0.17 mmol) and triethylamine (1.45 ml, 10 mmol). The reaction mixture was stirred for 2.5 h at ambient temperature, poured into a solution of aqueous 10% KHSO4/ice water 1/1 and extracted two times with ether. The combined extracts were washed with aqueous 10% KHSO4 and aqueous 10% NaCl and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 1.13 g (3.2 mmol, 93%) of the title compound as yellow oil.
Reaction SMILES: C1(=O)[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:7]2=[O:25])C(=O)C2=CC=CC=C12.CNN>C(COC)OC>[NH2:5][C@H:6]1[C@@H:9](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19])[C:7]1=[O:25]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)[C@H]1/C=C/c1ccccc1
Agent: CNN
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](N)[C@H]1/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 5 ml of dimethoxyethane is suspended 440 mg of cis-3-phthalimido-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine and after addition of 0.26 ml of methylhydrazine, the mixture is stirred at room temperature for 30 minutes. The solvent is then distilled off under reduced pressure and the residue is dissolved by addition of 5 ml of methylene chloride and allowed to stand overnight. The precipitate is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography [eluent: chloroform-ethyl acetate (6:4)] to give an oil of cis-3-amino-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine. This oil is dissolved in 10 ml of tetrahydrofuran and under ice-cooling and stirring, 0.2 ml of triethylamine is added, followed by addition of 0.212 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride hydrochloride. The mixture is stirred under ice-cooling for 10 minutes and then at room temperature for 30 minutes, after which the reaction mixture is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is purified by silica gel column chromatography [eluent: chloroform-ethyl acetate (7:3)] and crystallized from ether to give cis-[2-(2 -chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine (syn-isomer), melting at 228°-231° C. (decomp.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C(N(CC)CC)C.Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[BH4-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCN
Reactant: O=Cc1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thiophene aldehyde (11.2 g) was dissolved in 100 mL of methanol, then 12.1 g of triethylamine and 16.1 g of ethyl 3-aminopropionate hydrochloride were added thereto in this order and the mixture was stirred overnight at room temperature. The reaction solution was cooled down to 0° C., 2.27 g of sodium borohydride was slowly added thereto little by little and the mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [C:1]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22]>[60Co]>[C:21]([CH:20]([C:19]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])(=[O:22])[CH3:23]
Reactant: C=CCCCCCCCCC(=O)N1CCOCC1
Reactant: CCOC(=O)CC(C)=O
Agent: [60Co]
Product: CCOC(=O)C(CCCCCCCCCCC(=O)N1CCOCC1)C(C)=O

Procedure:
Samples of 2 grams (.0078 mole) of 10-undecenoylmorpholine and 30.9 grams (0.237 mole) of ethyl acetoacetate were placed in a flask, mixed well, and exposed to a cobalt-60 (γ-radiation) source to initiate free radical chain reaction. After irradiating for 17 hours, the mixture was removed from the irradiation source and stripped under reduced pressure. Analysis of the product, N-(12-acetyl-12-carboethoxydodecanoyl) morpholine: % G 65.78 (theory 65.76); % H, 9.87 (theory 9.73); % N, 3.68 (theory 3.65).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[NH:22][CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4.Cl.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:22]([C:31](=[O:33])[CH3:32])[CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4
Reactant: ClCCCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCCCl)cc13
Temperature: 25 °C
Yield: 82 %

Procedure:
To a stirred solution of 3-(3-chloropropyloxy)morphinan.HCl 54 (3 mg, 0.008 mmol) and triethylamine (7 μL, 0.050 mmol) in dry dichloromethane (0.3 mL) was added acetyl chloride (1.8 μL, 0.025 mmol) and the mixture was stirred at room temperature. After starting material disappeared on TLC, solvent was concentrated and column chromatography gave 2.5 mg (82%) of the title compound: 1H NMR (300 MHz, CDCl3) δ6.96 (1H, t); 6.83 (1H, d); 6.75 (1H, d. d.); 4.92 (1H, m); 4.15 (2H, t); 3.81 (2H, t); 3.75 (1H, m); 3.12 (1H, m); 2.95 (1H, m); 2.62 (1H, m); 2.30 (1H, m); 2.18 (2H, m); 2.05 (3H, s); 1.00˜1.80 (10H, m).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C@@H:13]([O:27][CH3:28])[CH2:12]1)=O)C1C=CC=CC=1.[NH2:29][C:30]1[C:39]([F:40])=[C:38](F)[C:37](C)=[C:36]2[C:31]=1[C:32](=[O:50])[C:33]([C:47]([OH:49])=[O:48])=[CH:34][N:35]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:29][C:30]1[C:39]([F:40])=[C:9]([N:11]2[CH2:15][C@H:14]([C:16]3([NH2:19])[CH2:17][CH2:18]3)[C@@H:13]([O:27][CH3:28])[CH2:12]2)[C:37]([CH3:38])=[C:36]2[C:31]=1[C:32](=[O:50])[C:33]([C:47]([OH:49])=[O:48])=[CH:34][N:35]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46]
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CO[C@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn([C@@H]4C[C@@H]4F)c3c2C)C[C@@H]1C1(N)CC1
Reaction time: 4 h
Yield: 15.9 %

Procedure:
1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(R)-methoxypyrrolidine (550 mg, 1.41 mmol) was dissolved in ethanol (40 ml), and the solution was mixed with a 5% palladium-carbon catalyst (water content, 55.6%; 550 mg) and stirred for 4 hours under a pressured hydrogen atmosphere (4.5 kg/cm2). The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (5 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (249.8 mg, 0.80 mmol) and triethylamine (3 ml) and stirred for 2 days in an oil bath of 120° C. under a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved-in chloroform (100 ml) and washed with a 10% citric acid aqueous solution (50 ml×2) and saturated brine (100 ml) in that order and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (10 ml), followed by 1 hour of stirring at room temperature. After adding water (20 ml) to the reaction solution, the aqueous solution was washed with dichloromethane (50 ml×3), adjusted to pH 11 with sodium hydroxide aqueous solution and then washed with dichloromethane (50 ml×2). This was adjusted to pH 7.4 with concentrated hydrochloric acid and extracted with chloroform (150 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to preparative silica gel thin layer chromatography (development with the bottom layer of a mixture of chloroform:methanol:water=7:3:1), and the resulting crude product was purified by recrystallizing from ethanol-diisopropyl ether and then dried under a reduced pressure to obtain 57 mg (16%) of the title compound as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
5-chloroisatin (0.09 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C([C@H]1[C@H](N)C2[CH:30]=[CH:31][S:32]C=2CC1)CC>>[CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[CH:30]=[CH:31][S:32][C:19]=3[CH2:18][CH2:17][C@H:16]2[CH2:15][CH2:14][CH3:13])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCC[C@@H]1CCc2sccc2[C@H]1N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting trans-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.66, 7.08, 6.44, 5.19, 4.46, 2.82, 2.68–2.52, 2.03, 1.94, 1.78, 1.53–1.48, 1.26, 0.92; HRMS (FAB) calcd for C19H27N3S+H 330.2004, found 330.1993.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[N:15]=[C:14]2[NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>CN1C(=O)CCC1.CO>[N:4]1([CH2:3][CH2:2][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH2:32])=[O:31])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: ClCCN1CCCCC1
Reactant: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(O)cc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN1CCCC1=O
Solvent: CO
Product: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(OCCN3CCCCC3)cc12
Temperature: 90 °C

Procedure:
To 1-(2-chloroethyl)piperidine (45 μmol) was added the solution of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (30 μmol) in NMP (200 μL) PS-BEMP (90 μmol) was added to the vials by resin dispenser. After the reaction mixture was heated at 90° C. for 12 h, the residue was diluted with methanol and purified by mass triggered PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28](=[CH:20][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=3[CH3:1])[C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: COc1ccc2c(c1)NC(=O)C2
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c2c(c1C)C(=O)N(CCN1CCCCC1)CC2
Yield: 61.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 6-methoxy-1,3-dihydro-indol-2-one (prepared according to Journal of Organic Chemistry, 70(5), 1828-1834, 2005) starting materials to give 2-(6-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (51 mg, 61.8%) as an orange solid.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].C([Mg]Br)(C)C.Cl>O>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]([OH:11])[CH:3]([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: COc1ccccc1C=O
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: O
Product: COc1ccccc1C(O)C(C)C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
Dry tetrahydrofuran (3 mL) was added to 1.01 g (7.43 mmol) of commercially available 2-methoxybenzaldehyde under nitrogen atmosphere, and the mixture was ice-cooled. To the mixture was added dropwise a 3.8 mL (7.6 mmol) of tetrahydrofuran solution containing 2 mol/L isopropylmagnesium bromide. After completion of dropwise addition, the reaction mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water, made acidic with diluted hydrochloric acid, and then, extracted with ether. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 1.00 g (5.56 mmol, Yield: 74.8%) of 1-(2-methoxyphenyl)-2-methyl-1-propanol.