Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc(-c2ccccc2)cc2ccccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc(-c5ccccc5)cc5ccccc45)cc3CC[C@@H]12
Yield: 41.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (86 mg, 0.33 mmol), potassium carbonate (158 mg, 1.14 mmol), 1-chloro-3-phenyl- isoquinoline (95 mg, 0.40 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 64 mg (42%) of the title compound as an off white solid. mp 183°-189°. FDMS: m/e=464. α[D]589 =+54.61 (c=0.53, chloroform).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([C:7]1[S:33][C:10]2[N:11]=[C:12]([NH2:32])[N:13]=[C:14]([C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH:23](OCC)[O:24]CC)[C:18]([Cl:30])=[CH:17][C:16]=3[Cl:31])[C:9]=2[CH:8]=1)=[O:6])[CH3:3].ClCCl.[BH4-].[Na+]>C1COCC1>[CH2:2]([NH:4][C:5]([C:7]1[S:33][C:10]2[N:11]=[C:12]([NH2:32])[N:13]=[C:14]([C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH2:23][OH:24])[C:18]([Cl:30])=[CH:17][C:16]=3[Cl:31])[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCNC(=O)c1cc2c(-c3cc(OCC(OCC)OCC)c(Cl)cc3Cl)nc(N)nc2s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)c1cc2c(-c3cc(OCCO)c(Cl)cc3Cl)nc(N)nc2s1
Reaction time: 18 h

Procedure:
Hydrochloric acid was added to a solution of 2-Amino-4-(2,4-dichloro-5-(2,2-diethoxyethoxy)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in THF and the solution stirred for ˜18 hrs. Dichloromethane was added and the mixture stirred, sodium borohydride was added and the resulting suspension stirred for ˜5 hrs. Dichloromethane was added and the mixture washed with saturated ammonium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a pale yellow solid. The crude product was purified by preparative HPLC, to give the product as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[C:18]([O:25][CH3:26])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[N:14]=1>>[CH3:26][O:25][C:18]1[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[C:15]([NH:27][C:28]1[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=1)[N:14]=[C:13]2[O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Product: COc1ccc2c(Oc3ccc(NC(C)=O)cc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[5,6-dimethoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 434(MH+).
Reaction SMILES: CN(C=O)C.[NH:6]1[C:39](=[O:40])[C@H:38]2[CH2:41][CH2:42][CH2:43][N:37]2[C:35](=[O:36])[C@H:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:26][C:24](=[O:25])[C@H:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][C:13](=[O:14])[C@@H:7]1[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].Cl.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(O)(=O)C>[NH:6]1[C:39](=[O:40])[C@H:38]2[CH2:41][CH2:42][CH2:43][N:37]2[C:35](=[O:36])[C@H:27]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:26][C:24](=[O:25])[C@H:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][C:13](=[O:14])[C@@H:7]1[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:45]([CH3:46])=[O:47]
Reactant: NCCCC[C@@H]1NC(=O)[C@H]2CCCN2C(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2ccccc2)NC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)NCCCC[C@@H]1NC(=O)[C@H]2CCCN2C(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2ccccc2)NC1=O
Reaction time: 2 h

Procedure:
To a DMF (2 ml) solution of the cyclo(-L-Lys-L-Phe-L-Phe-D-Pro-).HCl (44 mg, 80 mmol) obtained in step 10-1, TEA(33 ml, 0.24 mmol) and acetic anhydride (12 ml, 0.12 mmol) were added under ice cooling and stirred for 2 hours. The reaction mixture was neutralized by addition of acetic acid and concentrated. The crude peptide was preparatively purified by reverse-phase HPLC (column: YMC-Pack ODS A-323, 10×250 mm, 30% CH3CH/0.1% TFA) and lyophilized to yield 57 mg (quant) of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCCC1NCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with benzylamine (2.10 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product, 2-benzylamino-cyclopentanecarboxylic acid ethyl ester (2.10 g, 8.49 mmol, 44.2%), as a light yellow oil. LC-MS (ESI) calcd for C15H21NO2 247.16, found 248.2 [M+H+].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][C:15]3[N:14]4[CH2:18][CH2:19][C:20](=[CH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]4=[CH:12][C:11]=3[CH:10]=2)O1.[OH-:30].[Na+].OO.Cl>C1COCC1>[OH:30][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C:20](=[CH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3=[CH:12][C:11]=2[CH:10]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(O)ccc12
Yield: 78.1 %

Procedure:
To a solution of tert-butyl 2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (330 mg, 0.835 mmol) in THF (10 mL) was added a 2.0 M aqueous solution of sodium hydroxide (4.17 mL, 8.35 mmol). Then was added dropwise hydrogen peroxide (30 wt % aqueous solution, 0.853 mL, 8.35 mmol). The mixture was stirred at 23° C. for 25 min before 0.5 M HCl (50 mL) was added. The resulting mixture was extracted with dichloromethane (2×35 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography to provide the title compound as a pale yellow solid (186 mg). LCMS m/z=286.3 [M+H]+.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[NH2:8][C:9]1[S:10][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:13]=1[C:14]([NH2:16])=[O:15]>ClCCl>[CH2:17]([C:11]1[S:10][C:9]([NH:8][C:6]([NH2:5])=[O:7])=[C:13]([C:14]([NH2:16])=[O:15])[CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NC(=O)c1cc(Cc2ccccc2)sc1N
Solvent: ClCCl
Product: NC(=O)Nc1sc(Cc2ccccc2)cc1C(N)=O
Yield: 67.6 %

Procedure:
Chlorosulfonyl isocyanate (0.09 mL, 1.03 mmol) was added dropwise under nitrogen to a solution of 2-amino-5-benzyl-thiophene-3-carboxylic acid amide (0.2 g, 0.86 mmol) in dry dichloromethane (9 mL) at 0° C. and. The temperature of the resulting stirred reaction mixture was slowly raised from 0° C. to room temperature over 1 h. Once the LC-MS showed no starting material remaining, the reaction was quenched with water (1 mL) and stirred for 10 additional min. The solvent was removed under vacuum and the residue was taken up into DMSO (2 mL) and purified utilizing a Gilson preparative HPLC to give the above titled compound as a light brown solid (0.16 g, 67%). LC-MS [M+H]+ m/z 276.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([NH:15][C@H:16]([C@@H:20]([OH:22])[CH3:21])[C:17]([OH:19])=O)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:14])[NH:15][C@H:16]2[C:17](=[O:19])[O:22][C@H:20]2[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCCCCC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 39.6 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-2-(5-cyclohexylpentoxycarbonylamino)-3-hydroxy-butanoic acid (0.32 g, 1.02 mmol) in dry CH2Cl2 (30 mL), Et3N (0.43 mL, 3.08 mmol) and subsequently TBTU (0.39 g, 1.2 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 0:100) to afford the title compound (0.12 g, 39%) as white solid. MS (ESI) m/z: 298 [M−H]+; (ESI) m/z: 296 [M−H]−. 1H NMR: δ 0.78-0.93 (m, 2H), 1.05-1.33 (m, 10H), 1.36 (d, J=6.4 Hz, 3H), 1.51-1.72 (m, 7H), 3.92-4.09 (m, 2H), 4.86 (dq, J=6.3 Hz, 1H), 5.42 (dd, J=6.1, 9.4 Hz, 1H), 8.20 (d, J=9.4 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:13][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(O[Si](C)(C)C(C)(C)C)c(C=O)c1
Reaction time: 15 h
Yield: 114.3 %

Procedure:
To a stirred solution of 5-tert-butyl-2-hydroxybenzaldehyde (570 mg, 3.2 mmol) in DMF (5 mL) was added imidazole (435 mg, 6.4 mmol) and TBSCl (576 mg, 3.8 mmol). The reaction mixture was stirred for 15 h and quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layer was washed with H2O, brine, dried with Na2SO4 and concentrated under reduced pressure to provide 5-tert-butyl-2-(tert-butyldimethylsilyloxy)benzaldehyde (1.07 g, quantitative).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C1COCC1.O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: N#CCc1cccc(Br)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(C#N)c1cccc(Br)n1
Temperature: -78 °C

Procedure:
(6-Bromopyridin-2-yl)acetonitrile (Example 235, Step 1) (500 mg, 2.54 mmol) was dissolved in THF (10 mL) and cooled to −78° C. LHMDS (1.0 M in THF, 3.05 ml, 3.05 mmol) was added dropwise, and the solution was maintained at −78° C. for 20 minutes. A solution of (2-bromoethoxy)-tert-butyldimethylsilane (600 μL, 2.79 mmol) in THF (5.0 mL) was added dropwise over 5 minutes. The resulting mixture was maintained at −78° C. for 2 hours and warmed to room temperature overnight. The solution was then diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. Silica gel chromatography (0-15% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10](S(C3C=CC=CC=3)(=O)=O)[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].CO.[OH-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2[nH]ccc2c1
Yield: 85.5 %

Procedure:
To a stirred suspension of 5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (10.2 g, 33 mmol) in methanol (250 mL) powdered sodium hydroxide (2 g, 50 mmol) was added. After stirring at room temperature for 30′ more powdered sodium hydroxide (2 g, 50 mmol) and dichloromethane (50 mL) were added and stirring was prolonged for additional 30′. After concentration, a solution of 2N HCl (50 mL) and water (200 mL) was added and the obtained mixture was filtered. The yellow cake was washed with water and dried to give 5-nitro-1H-pyrrolo[2,3-b]pyridine (4.6 g, 28.2 mmol, 85% yield).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([CH3:31])[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:19]3[CH:18]=[C:17]([CH3:31])[CH:22]=[CH:21][CH:20]=3)=[O:29])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][S:20](=[O:23])[CH2:19][CH2:18]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[OH:24][CH2:25][CH2:26][NH2:27]>>[OH:24][CH2:25][CH2:26][NH:27][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][S:20](=[O:23])[CH2:19][CH2:18]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(N4CCCC4)ncnc23)CC1
Reactant: NCCO
Product: O=S1CCN(c2nc(NCCO)nc3c(N4CCCC4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 3 from 2-chloro-4-(1-oxido-thiomorpholino)-8-pyrrolidinopyrimido[5,4-d]pyrimidine (melting point: 243°-244° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH3:15])[C:12](=[O:14])[N:13]=1.[Li+].CC([N-]C(C)C)C.[CH3:24][C:25]([CH3:27])=[O:26]>C1COCC1>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([C:25]([OH:26])([CH3:27])[CH3:24])([CH3:15])[C:12](=[O:14])[N:13]=1
Reactant: CC(C)=O
Reactant: CC1SC(N[C@H]2C[C@@H]3CC[C@H]2C3)=NC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)C1(C)SC(N[C@H]2C[C@@H]3CC[C@H]2C3)=NC1=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one (1.10 g, 5.0 mmol) in THF (5 ml) at −78° C. was added LDA (2.0 M, 10 ml). After 5 min, acetone was added, and the reaction mixture was stirred for 1 h at −78° C. The resulting reaction mixture was poured into a sat'd NaH2PO4, and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (4:1; Hexane:EtOAc) to give the title compound as a white solid. MS (ES+): 283 (M+H)+. The diastereomers were separated using standard HPLC methods described within this text.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])[CH:12]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:36])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.165 mL, 0.165 mmol) was added to a solution of {5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 133-(1); 29.1 mg, 0.055 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol=10:4) to give the target compound as a colorless oil (15.7 mg, 56%).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([CH3:22])([CH3:21])[C:17](OC)=[O:18])[N:15]=2)[N:12]=1.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([CH3:22])([CH3:21])[C:17]([O:26][CH:23]([CH3:25])[CH3:24])=[O:18])[N:15]=2)[N:12]=1
Reactant: CC(C)O
Reactant: COC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1

Procedure:
In 18 ml of isopropanol, 995 mg of concentrated sulfuric acid was dissolved; 1.0 g of methyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was added, followed by thermal refluxing for 40 hours. After cooling, the mixture was concentrated under reduced pressure, neutralized by the addition of aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure; the crystal precipitated was collected, washed with hexane and dried to yield 794 mg of the title compound. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (5:1). The desired fraction was collected and dried to yield 215 mg of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.[CH3:18][NH:19][CH3:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:18][N:19]([CH3:20])[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCCl
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C)CCCN1CCSc2cc([N+](=O)[O-])ccc21
Yield: 41.5 %

Procedure:
A solution of 4-(3-chloropropyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.7 g, 2.57 mmol), dimethylamine (2M solution in THF) (2.57 mL, 5.13 mmol), potassium iodide (0.426 g, 2.57 mmol), and potassium carbonate (1.773 g, 12.83 mmol) in dry acetonitrile (20 mL) was stirred at 80° C. for 6 hours in a sealed tube. The reaction was then brought to room temperature and diluted with water (60 mL), and the product was extracted into ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (1:9 (2 M NH3 in MeOH):CH2Cl2) on silica gel to obtain the title product (0.3 g, 42%) as a thick syrup. 1H NMR (DMSO-d6) δ 7.85-7.80 (m, 2H), 6.85 (d, 1H, J=8.7 Hz), 3.77 (t, 2H, J=5.1 Hz), 3.47 (t, 2H, J=7.2 Hz), 3.06 (t, 2H, J=5.1 Hz), 2.24 (t, 2H, J=6.6 Hz), 2.14 (s, 6H), 1.75-1.65 (m, 2H); ESI-MS (m/z, %): 282 (MH+, 100).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[F:16][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[C:13]2[C:8]=1[N:7]([CH2:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2c(C)ccc(F)c2[nH]1
Product: Cc1ccc(F)c2c1cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 7-fluoro-4-methyl-1H-indole-2-carboxylic acid ethyl ester (Lit. 8) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 332.0 ([M−H]−).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2](=[O:1])[CH2:11]2)=[O:14])=[CH:21][CH:22]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C1CC(C(=O)O)c2ccccc2N1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CC(=O)Nc3ccccc32)cc1
Yield: 52.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide (0.6 g) was obtained. melting point: 170° C.
Reaction SMILES: Cl.[CH3:2][NH2:3].[Na].F[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]>C1COCC1>[CH3:2][NH:3][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: CN
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: CNc1ccccc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 95.2 %

Procedure:
Methylamine hydrochloride (2.7 g) and a 10% aqueous solution of sodium hydroxyde (30 ml) were added to a solution of 1-fluoro-2-nitrobenzene (2.82 g) in THF (20 ml). The mixture was kept at 23° for 24 h. The reaction mixture was then concentrated in vacuo, taken up with 10% aqueous sodium hydroxide (30 ml) and extracted with EA (3×30 ml). The combined organic layers were washed with a saturated ammonium chloride solution (50 ml), brine (50 ml) and dried. Evaporation of the solvent gave the title compound as an orange oil (2.894 g).