Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH3:42][C:43]1([CH3:52])[CH2:48][CH:47]([NH2:49])[CH2:46][C:45]([CH3:51])([CH3:50])[NH:44]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:49][CH:47]5[CH2:48][C:43]([CH3:52])([CH3:42])[NH:44][C:45]([CH3:51])([CH3:50])[CH2:46]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CC(C)(C)NC(C)(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.12 mL (0.66 mmole) of ethyldiisopropyl amine and 0.039 g (0.25 mmole) of 2,2,6,6-tetramethyl-piperidin-4-ylamine in 2.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.065 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2,2,6,6-tetramethyl-piperidin-4-yl)-benzamide (I-65) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](#[N:20])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([C:18]#[N:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: N#C[C@H]1CCN(Cc2ccccc2)C1
Temperature: 65 °C
Yield: 85 %

Procedure:
(R)-1-Benzyl-3-mesyloxypyrrolidine (5.0 g, 20 mmol) was dissolved in acetonitrile (6 mL) and tetrabutylammonium cyanide (11.1 g, 41.4 mmol) was added. The mixture was heated at 65° C. for 3 hours and then cooled to room temperature and extracted with ethyl ether (100 mL). The organic layer was washed with saturated NaHCO3 (2×50 mL), dried over MgSO4, and concentrated under reduced pressure to give (S)-1-benzyl-3-cyanopyrrolidine (3.1 g, 85%) as a yellow oil: VPC: 100%; 1HNMR (CDCl3, 60 MHz): δ1.9-2.4 (m, 2H), 2.5-3.1 (m, 5H), 3.60 (s, 2H), 7.30 (s, 5H).
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:25][OH:26])[O:23]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C/C=C\CCCCCCCC.C(OCC(CO)O)C1C=CC=CC=1.[Si:40](Cl)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:20][CH2:21][CH:22]([CH2:25][O:26][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO)OC
Agent: CN(C)c1ccncc1
Agent: OCC(O)COCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Reaction time: 3 h
Yield: 100 %

Procedure:
1-O-Oleoyl-2-O-methyl-rac-glycerol (Compound 44) To a mixture of 1-O-benzyl-glycerol (27 mL, 0.16 mol) and t-butyldimethylsilyl chloride (25 g, 0.17 mol) in dry CH2Cl2 (250 mL) under N2 was added DMAP (0.8 g, 6.6 mmol) followed by the addition of TEA (23 mL, 0.17 mol). After 3 hours, the mixture was washed with H2O (2×100 mL), dried (MgSO4) and concentrated to give 1-O-benzyl-3-O-t-butyldimethylsilyl-rac-glycerol (40) (48.8 g, 100%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:7][CH2:8][CH:9]([OH:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1>CN(C)P(N(C)C)(N(C)C)=O>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][O:16][CH:9]([CH2:8][O:7][C:6]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:4]([Cl:3])[CH:5]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: OC(COc1ccc(Cl)c(Cl)c1)Cn1ccnc1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Clc1ccc(COC(COc2ccc(Cl)c(Cl)c2)Cn2ccnc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 56% dispersion of sodium hydride in mineral oil (240 mg.) is added under nitrogen to a solution of 1.43 g. of 1-[3'-(3",4"-dichlorophenoxy)-2'-hydroxypropyl]imidazole in 4 ml. of dry hexamethylphosphoramide. The reaction mixture is then stirred for 1 hour at 25° C., and then 1 hour at 45° C. The solution is then cooled in an ice bath and 1.07 g. of α,3,4-trichlorotoluene in 1 ml. hexamethylphosphoramide is added dropwise with stirring. The reaction mixture is then stirred for 1 hour at 5° C., and then for 1 hour at 25° C., and finally for 2 hours at 45° C. The mixture is then poured into 100 ml. of water and the resultant aqueous mixture extracted with ether and the ether extracts washed with water. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue is chromatographed on silica gel and eluted with 30% acetone in dichloromethane to yield pure 1-[2'-(3",4"-dichlorobenzyloxy)-3'-(3",4"-dichlorophenoxy)propyl]imidazole which is taken up in ether and treated with nitric acid yielding, after recrystallization of the crude salt from ethyl acetate/ether, 1-[2'-(3",4"-dichlorobenzyloxy)-3'-(3",4"-dichlorophenoxy)propyl]imidazole nitrate, m.p. 116°-118.5° C.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([CH3:12])[C:5]=2[N:6]=1.N([O-])=O.[Na+].[Na+].[Cl-:18]>OP(O)(O)=O.O>[Cl:18][C:2]1[S:3][C:4]2[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([CH3:12])[C:5]=2[N:6]=1
Reactant: Cc1ccc(Cl)c2sc(N)nc12
Reactant: [Cl-]
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cl)c2sc(Cl)nc12
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a slurry of 2-amino-4-methyl-7-chlorobenzothiazole (77.2) (6.37 g) in H3PO4 (85%, 213 ml) in a 500 ml 3-necked flask with mechanical stirring and an internal temperature of <−10° C., was added dropwise a solution of NaNO2 (6.87 g) in water (11 ml). The mixture was warmed to 0° for 30 minutes and then recooled. The slurry was then slowly added to a cold (˜5° C.) solution of CuSO4.5H2O (32 g) and NaCl (40 g) in water (128 ml) with vigorous mechanical stirring. After the foaming subsides and warming to RT, the solids were collected by filtration and rinsed with water. The solids were dissolved in ether leaving some insoluble residue. The ether solution was washed with water, and sodium bicarbonate solution. After the organic layer was concentrated, the residue was purified by flash chromatography with 10% methylene chloride in hexane to afford 2-chloro-4-methyl-7-chlorobenzothiazole (77.3) (4.48 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O)=[O:10].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8])=[O:10]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Clc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1-c1ccccc1Cl

Procedure:
To a solution of 2-bromochlorobenzene (0.12 mL, 1 mmol) and 2-formylbenzeneboronic acid (0.17 g, 1.1 mmol) in toluene (9 mL) were added 2M aq. sodium carbonate (1.2 mL) followed by (Ph3P)4Pd (0.34 g, 0.3 mmol). The resulting reaction mixture was refluxed for 3 h, cooled and diluted ethyl acetate. The organic phase was washed with water, saturated aq. sodium bicarbonate, brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the residue obtained was purified by chromatography (hexane:ethyl acetate; 4:1) to yield the title product.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Cl:8][C:7]1[C:2]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2nccnc2Cl)cc1
Reaction time: 8 h

Procedure:
To a round-bottomed flask was added 2,3-dichloropyrazine (7.3582 g, 49.4 mmol), 4-aminophenol (5.39 g, 49.4 mmol), and cesium carbonate (48.3 g, 148 mmol) in DMSO (165 mL) at 110° C. to stir overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, sat NaCl, sat sodium bicarbonate, dried with magnesium sulfate, filtered, and concentrated to give the title compound. MS (ESI, pos. ion) m/z: 222.1.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C(=O)(O)[O-].[Na+].O.Br[CH2:12][C:13]([CH2:15][C:16]([NH:18][CH:19]1[C:39](=[O:40])[N:21]2[C:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[CH:23][CH2:24][S:25][C@H:20]12)=[O:17])=O>O1CCCC1>[NH2:1][C:2]1[S:3][CH:12]=[C:13]([CH2:15][C:16]([NH:18][CH:19]2[C:39](=[O:40])[N:21]3[C:22]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=4)=[O:27])=[CH:23][CH2:24][S:25][C@H:20]23)=[O:17])[N:4]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Thiourea (1.13 g), sodium bicarbonate (1.24 g) and water (20 ml) were added to a solution of 4-nitrobenzyl 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate (6.15 g) in tetrahydrofuran (60 ml), and stirred at room temperature for an hour. After concentrating the resultant solution under reduced pressure, the residue was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to column chromatography on silica gel, and eluted with benzene, a mixture of benzene (1 part) and ethyl acetate (1 part) and then ethyl acetate in turn. The ethyl acetate fractions were collected and concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylate (1.5 g).
Reaction SMILES: [Li][CH3:2].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:35])([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:37])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:35])([C:21]4[CH:28]=[CH:27][C:24]([CH:25]([OH:26])[CH3:2])=[CH:23][CH:22]=4)[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:37])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [Li]C
Reactant: Cn1cncc1C(O)(c1ccc(C=O)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3C)c2cncn2C)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
MeLi (0.00258 mol) was added dropwise at −70° C. to a solution of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5yl)methyl]benzaldehyde (described in Example B6) (0.001 mol) in THF (5 ml) under N2 flow. The mixture was stirred at −70° C. for 2 hours. H2O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.9 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 95/5/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.3 g (58%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(1-hydroxyethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, mp. 181° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:7]=1)[CH3:4].Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:29]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:29]=3)=[CH:23][CH:24]=2)[N:7]=1)[CH3:4]
Reactant: ClCc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccc(-c4ccccc4)n3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (478 mg) and 2-chloromethyl-6-phenylpyridine (306 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(6-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (689 mg, yield: 95%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:15]O>S(=O)(=O)(O)O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:15])=[O:11]
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1C(F)(F)F

Procedure:
A solution of 2-trifluoromethylphenylacetic acid (5.0 g) in methanol (30 ml) containing 5 drops of concentrated sulphuric acid was heated at reflux for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate (100 ml), washed with 1N sodium hydroxide (25 ml) then with brine (25 ml), dried over magnesium sulphate and evaporated to give the title compound (5.04 g) as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])=[CH:8][CH:7]=1)[CH3:2].Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:13](=[O:21])[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:24]2=[O:26])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2ccccc2N)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4-(2-amino-benzoylamino)-phenyl]-acetic acid ethyl ester (14.2 g, 47 mmol) and triphosgene (0.5 eq, 7.03 g, 23.5 mmol) in DCM (200 ml) is treated with DIPEA (2 eq, 16.5 ml, 94 mmol) dropwise via dropping funnel while stirring at RT. After 1 hour, the reaction mixture is diluted with DCM and washed with saturated aqueous NaHCO3. The separated organic layer is washed with distilled water (2×), dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained as pure white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](O)=[O:22])[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4].[N:37]1([CH2:43][CH2:44][CH2:45][NH2:46])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:22])[NH:46][CH2:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2cccc(C(=O)O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Reactant: NCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(-c2cccc(C(=O)NCCCN3CCOCC3)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution (2 ml) of 4-(3-carboxyphenyl)-6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-morpholin-4-ylpropylamine (31 μl) in acetonitrile were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg) and 4-hydroxybenzotriazole monohydrate (38 mg) at room temperature with stirring and the mixture was stirred at room temperature for 12 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried and concentrated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1) to give the title compound (93 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].Br[CH2:27][C:28]([OH:30])=[O:29]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)[CH:5]=[C:6]([CH3:9])[C:7]=1[O:8][CH2:27][C:28]([OH:30])=[O:29]
Reactant: O=C(O)CBr
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
A solution of 3-(3,5-dimethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (350 mg, 0.988 mmol, Intermediate 10) in isopropanol (5 mL) and 3 N aq. NaOH (1.5 mL) is treated with bromoacetic acid (274 mg, 1.98 mmol). The dark red reaction mixture is stirred at 70° C. After 1, 2, 3 and 18 h an additional portion of bromoacetic acid (274 mg, 1.98 mmol) and 3N aq. NaOH (1.5 mL) is added and stirring is continued for 2 h after the last addition. The reaction mixture is diluted with EA, and washed with 1 N aq. HCl. The aq. phase is extracted with EA. The combined organic extracts are dried over MgSO4 and evaporated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 10% of methanol to give {2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-acetic acid (60 mg) as a pale yellow oil; LC-MS: tR=1.07 min, [M+1]+=413.23.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[N:15]([C:16]2[S:20][C:19]([CH2:21][NH:22][C:23](=[O:34])[C@@H:24]([NH:26]C(=O)OC(C)(C)C)[CH3:25])=[CH:18][CH:17]=2)[N:14]=[C:13]([C:35]([F:38])([F:37])[F:36])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:26][C@@H:24]([CH3:25])[C:23]([NH:22][CH2:21][C:19]1[S:20][C:16]([N:15]2[C:11]([C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:12][C:13]([C:35]([F:36])([F:38])[F:37])=[N:14]2)=[CH:17][CH:18]=1)=[O:34]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a stirred solution of 26a (24 mg, 0.044 mmol) in CH2Cl2 (0.44 mL) was added trifluoroacetic acid (44 μL, 0.571 mmol). The mixture was stirred for 2 h at room temperature. The solvent was then evaporated and the residue was purified by silica gel column chromatography with gradient of MeOH (5-20%) in CH2Cl2. The residue was purified by prep-HPLC using an Aquasil C18 column with gradient of MeOH (5-95%) in water to afford 27a (7.7 mg, 39%) as a white solid. 1H NMR (DMSO-d6) δ(ppm): 9.41 (t, J=5.7 Hz, 1H), 8.69 (m, 1H), 8.28 (s, 1H), 7.41 (s, 1H), 7.33 (d, J=6.8 Hz, 2H), 7.28-7.24 (m, 3H), 7.05 (d, J=3.3 Hz, 1H), 6.86 (d, J=3.9 Hz, 1H), 4.44 (m, 2H), 4.40 (d, J=5.9 Hz, 2H), 3.44 (q, J=6.8 Hz, 1H), 1.20 (d, J=6.8 Hz, 3H). LRMS: calc 451.1; found 452.5 (MH)+.
Reaction SMILES: C([NH2:4])(C)C.Cl.[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:23](=O)[CH3:24])[C:15](OC(C)C)=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]>O.CS(C)=O>[CH3:24][C@H:23]1[NH:4][C:15](=[O:16])[CH:14]([NH:13][C:11](=[O:12])[O:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:21][C@H:22]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32]
Reactant: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1ccccc1C
Reactant: CC(C)N
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccccc1[C@@H]1CC(NC(=O)OC(C)(C)C)C(=O)N[C@@H]1C
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 20728 %

Procedure:
To a solution of NaBO3.4H2O (10 g, 0.026 mol) in H2O (180 g) was charged isopropylamine (30 g, 0.25 mmol) dropwise at 20° C. After the mixture was stirred for 30 min, the pH was adjusted to 10.3-10.5 by 6M HCl. PLP (1 g, 6.4 mmol) and ATA-412 (25 g) was charged to the solution at 20° C. After the above mixture was stirred for 1 h, a solution of 36 (50 g, 4.7 mmoL) in DMSO (250 mL) was added slowly at 20° C. The solution was heated to 55° C. and stirred for 24 h. After the reaction was complete, the reaction was quenched by isopropyl alcohol (100 mL), and then partitioned with water and IPAc. The organic phase was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-20% EtOAc/PE) to give 37 (16.5 g, 40% yield). 1H (DMSO-d6, 400 MHz): δ 7.83 (s, 1H), 7.18-7.13 (m, 4H), 4.06 (br, 1H), 3.67-3.51 (m, 2H), 2.30 (d, 3H), 1.99 (t, 1H), 1.36 (s, 9H), 0.82 (m, 3H); MS (ESI) m/e [M+H]+: 319.2
Reaction SMILES: CO[C:3]([CH:5]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]2[C:6]1=[CH:7][C:8]([F:20])=[CH:9][C:10]=2[CH3:19])=[O:4].[H-].[Na+].I[CH2:24][C:25]([NH2:27])=[O:26]>O1CCCC1>[F:18][C:15]1[CH:16]=[C:17]2[C:5]3([CH2:24][C:25](=[O:26])[NH:27][C:3]3=[O:4])[C:6]3[C:11](=[C:10]([CH3:19])[CH:9]=[C:8]([F:20])[CH:7]=3)[C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)CI
Reactant: COC(=O)C1c2cc(F)cnc2-c2c(C)cc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)cc2c1-c1ncc(F)cc1C21CC(=O)NC1=O

Procedure:
Treatment of 3.7-difluoro-9-methyl-5H-indeno]1,2-b]pyridin-5-one with hydrazine in hot diethylene glycol provided 3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridine. Deprotonation using n-butyllithium in tetrahydrofuran followed by reaction with carbon dioxide and methanolic hydrogen chloride provided 3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridin-5-carboxylic acid methyl ester. The ester was then deprotonated using a slight excess of sodium hydride in tetrahydrofuran and treated with iodoacetamide to provide, after 18 hours at room temperature and 6 hours at reflux, the title compound.