Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7][OH:8]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reaction time: 2.5 h

Procedure:
A mixture of {4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (intermediate 1, 2.52 g) in chloroform (200 ml) was treated with manganese dioxide (17.3 g) and the reaction mixture stirred for 2.5 hours. The reaction was filtered through Celite™ and the filtrate evaporated to give the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:10]=1[O:11][C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[NH:14][N:13]=1.[C:27](Cl)(=[O:30])[O:28][CH3:29]>O1CCCC1>[CH3:29][O:28][C:27]([N:14]1[C:15]([CH3:21])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:12]([O:11][C:10]2[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:9]=2[CH3:8])=[N:13]1)=[O:30]
Reactant: COC(=O)c1c(Oc2cccc(C)c2C)n[nH]c1C
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(Oc2cccc(C)c2C)nn(C(=O)OC)c1C

Procedure:
A mixture of 5.6 g of triethylamine, 13 g of 3-(2',3'-dimethylphenoxy)-5-methyl-4-methoxycarbonyl pyrazole and 100 ml of tetrahydrofuran is prepared, and, while stirring and cooling, 4.9 g of methyl chlorocarbonate is dripped in. After stirring for 16 hours, the precipitated hydrochloride is filtered off. The filtrate is concentrated and the residue is recrystallized from ethyl acetate. Melting point: 115° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[ClH:20].[CH3:21][CH2:22]O>>[ClH:20].[NH2:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([O:12][CH2:21][CH3:22])=[O:11]
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCO
Agent: Cl
Product: C=CCCCCC[C@H](N)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of (2S)-2-[(t-butoxycarbonyl)amino]non-8-enoic acid (ACME Bioscience Inc) (1.00 g, 3.69 mmol) in EtOH (10 ml) was saturated with HCl gas. The mixture was stirred at RT for 2 hours, then concentrated to give the title product (0.85 g). LRMS (ESI) m/z 200.4 [(M+H)+; calcd for C11H22NO2: 200.2].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[N:17]=1)=[O:14].[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:23]1[CH2:24][CH:25]=[C:26]([C:18]2[N:17]=[C:16]([NH:15][C:13]([NH:12][C:7]3[C:6]4[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[O:14])[CH:21]=[CH:20][CH:19]=2)[CH2:27][CH2:28]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C(Nc1cccc(I)n1)Nc1ccnc2c(F)cccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C2=CCOCC2)n1)Nc1ccnc2c(F)cccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
1-(8-Fluoroquinolin-4-yl)-3-(6-iodopyridin-2-yl)urea (250 mg, 0.582 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (187 mg, 0.873 mmol), sodium carbonate solution (2M, 1.31 mL, 2.62 mmol) and tetrakis(triphenylphosphine)-palladium(0) (68 mg, 0.058 mmol) were dissolved in 5 ml of DMF under an argon atmosphere and the mixture was stirred at 80° C., in a microwave oven, for one hour. After the solvent had been evaporated down to dryness, the resulting residue was treated with water and the mixture was then extracted with ethyl acetate. After the combined organic phases had been dried over sodium sulfate and the solvent had been filtered and evaporated down to dryness, the resulting residue was purified by column chromatography to give the title product (50 mg, 19%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][N:9]1[C:13]([S:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)=[N:12][N:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][N:9]1[C:13]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[N:12][N:11]=[N:10]1
Reactant: Cn1nnnc1SCCCCBr
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCCSc1ccccn1
Yield: 75.9 %

Procedure:
2-Mercaptopyridine (1.3 g) and 1-methyl-5-(4-bromobutyl)thio-1,2,3,4-tetrazole (2 g) are dissolved in acetone (50 ml). To the mixture is added potassium carbonate (1.4 g), and the mixture is refluxed for 2 hours. After acetone is distilled off, water is added to the residue, and the precipitated crystals are separated by filtration and recrystallized from ethanol-water to give 1-methyl-5-[4-(2-pyridyl)thiobutyl]thio-1,2,3,4-tetrazole (1.7 g) as pale yellow prisms, m.p. 49°-51.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]2[CH2:11][O:12][CH3:13]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(N)c2n1COC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(Cl)ccc(NS(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a mixture of ethyl 7-amino-4-chloro-1-(methoxymethyl)-1H-indole-2-carboxylate (0.91 g) and pyridine (10 mL) was added thiophene-2-sulfonyl chloride (0.50 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (1.14 g, yield 83%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([OH:23])(=[O:22])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15]>C(O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([OH:23])=[O:22])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C(=O)O)c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: O=C(O)C(CN1CCN(c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C

Procedure:
1-Phenylpiperazine and atropic acid in ethanol is heated under reflux for 18 h, cooled to room temperature, and evaporated in vacuo. The solid is triturated with acetone to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[C:17]2[Cl:23].N1C=CC=CC=1>O>[Cl:23][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([NH:13][S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH:15]=2)[NH:19][N:18]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1ccc2[nH]nc(Cl)c2c1)c1ccc(Cl)c(Cl)c1
Yield: 4.7 %

Procedure:
N-(3-Chloro-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide can be obtained in the following way: a solution of 1.1 g of 3,4-dichlorobenzenesulfonyl chloride is added dropwise to a solution, cooled to 0° C. of 0.75 g of 5-amino-3-chloro-1H-indazole and of 14 ml of pyridine. After reacting for 10 minutes at a temperature in the region of 0° C. and 2 hours 30 minutes at a temperature in the region of 20° C., 50 ml of distilled water are added to the reaction medium. The medium is extracted with 50 ml and 25 ml of ethyl acetate. The organic phase is subsequently dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (99/1 by volume) mixture as eluent. The yellow oil thus obtained is again purified by chromatography on a silica column with dichloromethane as eluent. 0.08 g of N-(3-chloro-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide is thus obtained in the form of a thick white oil (analysis C13H8Cl3N3O2S % calculated C, 41.46; H, 2.14; Cl, 28.24; N, 11.16; O, 8.50; S, 8.51. % found C, 41.43; H, 2.58; N, 10.81; S, 7.84).
Reaction SMILES: Cl[CH:2]([CH:13]1[CH2:15][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1>CC#N>[CH:13]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=2)[N:18]2[CH2:19][CH2:20][NH:21][CH2:22][C@H:17]2[CH3:16])[CH2:15][CH2:14]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1cccc(C(Cl)C2CC2)c1
Solvent: CC#N
Product: C[C@@H]1CNCCN1C(c1cccc(C(F)(F)F)c1)C1CC1
Temperature: 90 °C
Yield: 96 %

Procedure:
A mixture of 1-(chloro(cyclopropyl)methyl)-3-(trifluoromethyl)benzene (2.5 g, 11 mmol) and (R)-2-methylpiperazine (3.2 g, 32 mmol) in 30 mL of MeCN was heated at 90° C. overnight. The solvent was evaporated and the solid residue was submitted to column chromatography (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:20) to give crude (2R)-1-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazine (3.15 g) which was directly used in next step.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:32])[CH2:7][N:8]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][CH:10]([N:28]=[N+]=[N-])[C:9]1=[O:31])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(Cl)Cl.CO.C(OCC)(=O)C.[Pd].[H+].[H+].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[K+].[I-].[Pt]>[C:1]([NH:5][C:6](=[O:32])[CH2:7][N:8]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][CH:10]([NH2:28])[C:9]1=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C1CC(N=[N+]=[N-])C(=O)N(CC(=O)NC(C)(C)C)C(c2ccccc2)C1
Agent: [Pd]
Agent: [Pt]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: Cc1ccccc1C1CC(N)C(=O)N(CC(=O)NC(C)(C)C)C(c2ccccc2)C1
Yield: 94.7 %

Procedure:
A solution of 13.7 grams (31.6 mmol) N-(t-butyl)-2-oxo-3-azido-5-(2-methylphenyl)-7-phenyl-2,3,4,5,6,7-hexahydroazepin-1-yl ethanoic amide in 120 mL ethanol and 60 mL methylene chloride was hydrogenated at 42 psi in the presence of 3.9 grams 10% palladium-on-carbon for 36 hours. The reaction showed Rf =0.30/0.15 iodoplatinate positive, in 30% methanol in ethyl acetate. It was filtered through Celite with ethanol and methylene chloride, evaporated, and chromatographed on silica gel using 15% and 30% methanol in ethyl acetate as eluant to afford 12.2 grams (95%) of a foam. 1H-NMR (δ, CDCl3): 1.13 (singlet, 9H), 2.0-2.5 and 3.9 (multiplets, 6H), 2.28 (s, 3H), 3.4 (m, 1H), 4.7 (m, 2H), 5.18 (d, J=10, 1H), 5.94 (broad singlet, 1H, NH), 7.0-7.3 (m, 9H). 13C-NMR (δ, CDCl3): 19.6, 28.6, 37.3, 38.7, 40.8, 48.2, 51.1, 53.5, 60.9, 126.0, 126.4, 128.6, 128.8, 129.8, 130.6, 134.8, 138.1, 143.0, 168.0, 174.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11](C3CCCCO3)[N:10]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.C(OC([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]([NH2:45])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[N:7][C:2]([NH:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:35]([CH:32]3[CH2:31][CH2:30][NH:29][CH2:34][CH2:33]3)=[CH:36][CH:37]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c3ccccc23)CC1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)nn1C1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(Nc3ccc(C4CCNCC4)c4ccccc34)ncc2Cl)n[nH]1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 2,5-dichloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine (202.7 mg, 0.62 mmol), tert-butyl-4-(4-aminonaphthalen-1-yl)piperidine-1-carboxylate (202.0 mg, 0.62 mmol), Xantophos (35.9 mg, 0.062 mmol), padallium acetate (II) (7.0 mg, 0.031 mmol), and cesium carbonate (40.3 mg, 0.12 mmol) in 5.0 mL of THF was heated at 150° C. in a microwave reactor for 25 min. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was dissolved in 5 mL of DCM and 4 mL of TFA. This reaction mixture was stirred at room temperature for 2 h followed by concentration in vacuo. The crude product is purified by RP-HPLC to afford 5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-(piperidin-4-yl)naphthalene-1-yl)pyrimidine-2,4-diamine; ESMS m/z 434.2 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([N:25]=[C:26]=[O:27])[CH2:23][CH3:24]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:26]([NH:25][CH2:22][CH2:23][CH3:24])=[O:27])[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)CC1
Reactant: CCCN=C=O
Solvent: ClCCl
Product: CCCNC(=O)NCCCCCN1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(4-tert-Butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (1.1 g) was dissolved in methylene chloride (20 ml) and a solution of n-propyl isocyanate (0.34 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure to give 4-tert-butoxycarbonylaminomethyl-1-(5-(3-n-propylureido)pentyl)piperidine.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:27]1[O:38][C:37]2[CH:36]=[CH:35][C:31]([CH2:32][CH2:33][NH2:34])=[CH:30][C:29]=2[O:28]1>ClCCCl>[C:10]([O:9][C:7](=[O:8])[NH:1][C@H:2]([C:4](=[O:6])[NH:34][CH2:33][CH2:32][C:31]1[CH:35]=[CH:36][C:37]2[O:38][CH2:27][O:28][C:29]=2[CH:30]=1)[CH3:3])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Boc-Ala-OH (222 mg, 1.20 mmol) was dissolved in DCE (4 mL), followed by addition of CDI (209 mg, 1.20 mmol). The mixture was stirred at room temperature for 30 min. 3,4-Methylenedioxyphenethylamine hydrochloride (240 mg, 1.20 mmol) and TEA (2.4 mmol) were added and the reaction was stirred at room temperature under Nitrogen for 16 hours. Next, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM and transferred to a separatory funnel and washed with saturated NaHCO3 (aq). The organic layer was dried with Na2SO4 and concentrated down. The crude material was purified by flash chromatography (DCM to 9:1 DCM/MeOH) to yield 350 mg (88%) of (S)—[1-(2-benzo[1,3]dioxol-5-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester. [M+H]+ 337.05.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH:12][C:13]1[CH:25]=[CH:24][C:16]2[O:17][C:18]([C:21](O)=[O:22])=[CH:19][O:20][C:15]=2[CH:14]=1>>[OH:12][C:13]1[CH:25]=[CH:24][C:16]2[O:17][C:18]([C:21]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:22])=[CH:19][O:20][C:15]=2[CH:14]=1
Reactant: CCCCNc1ccccc1
Reactant: O=C(O)C1=COc2cc(O)ccc2O1
Product: CCCCN(C(=O)C1=COc2cc(O)ccc2O1)c1ccccc1
Yield: 91 %

Procedure:
That compound is obtained in a yield of 91% starting from N-butylaniline and 6-hydroxy-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6]2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6]2
Reactant: COC(=O)C1Cc2ccc(OC)cc2C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C1Cc2ccc(O)cc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 5-methoxy-2,3-dihydro-1h-indene-2-carboxylate (696) (2.35 g, 11.4 mmol) in anhydrous dichloromethane (40 mL) cooled to −78° C. was added boron tribromide (1.5 eq.). The reaction was allowed to stir at −78° C. for 30 minutes, 0° C. for 2 hours, and at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched slowly with methanol. After stifling for 15 minutes a saturated sodium bicarbonate solution was added slowly to the mixture and allowed to stir at 0° C. for 30 minutes. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford methyl 5-hydroxy-2,3-dihydro-1H-indene-2-carboxylate (697).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:18](I)=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:23][C:20]1[N:19]=[CH:18][C:17]([O:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (229 mg), 3-hydroxy-2-iodo-6-methylpyridine (486 mg), and 4-dimethylaminopyridine (390 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. overnight. The reaction solution was cooled to room temperature and was then purified by column chromatography using acetone-chloroform to give the title compound (186 mg, yield 61%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH:27]1[CH2:30][N:29]([CH2:31][C@H:32]([O:43][C:44]2[N:49]=[CH:48][N:47]=[C:46]3[N:50]([C:53]4[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][N:54]=4)[N:51]=[CH:52][C:45]=23)[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=2)=[O:34])[CH2:28]1)(C(C)(C)C)(C)C>C1COCC1>[Cl:59][C:58]1[C:53]([N:50]2[C:46]3=[N:47][CH:48]=[N:49][C:44]([O:43][C@@H:32]([CH2:31][N:29]4[CH2:30][CH:27]([OH:26])[CH2:28]4)[C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=4)=[O:34])=[C:45]3[CH:52]=[N:51]2)=[N:54][CH:55]=[CH:56][CH:57]=1
Reactant: Cc1ccc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](CN2CC(O)C2)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.9 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.328 mL, 0.33 mmol) was added to (2S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate AD9) (195 mg, 0.33 mmol) in THF (2 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 6 hours. The reaction mixture was quenched with saturated NH4Cl, diluted with DCM and poured onto a phase separator. The organic layer was evaporated to a gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc to afford the product (38.0 mg, 24.12%). 1H NMR (400 MHz, CDCl3) δ 1.23-1.29 (1H, m), 2.29 (3H, s), 3.16-3.32 (4H, m), 3.76-3.87 (2H, m), 4.46-4.53 (1H, m), 5.91 (1H, t), 7.44-7.49 (1H, m), 7.50-7.55 (1H, m), 7.97-8.03 (1H, m), 8.07-8.15 (2H, m), 8.42 (1H, s), 8.59-8.65 (2H, m), 9.58 (1H, s) m/z (ES+) (M+H)+=481.51; HPLC tR=1.14 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>ClCCl>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: COc1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
The mixture of 3-methoxyaniline (3.7 g), ethyl bromoacetate (5 g) and triethylamine (4 g) in dichloromethane (30 mL) was stirred at room temperature for overnight. The mixture was washed with water (50 ml), dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 1.7 g of (3-methoxy-phenylamino)-acetic acid ethyl ester. 1HNMR: δ 1.33 (3H), 3.796 (3H), 3.92 (2H), 4.26 (2H), 6.21 (1H), 6.29 (1H), 6.36 (1H), 7.13 (1H).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:29]#[N:30])[C:22]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:31])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:29]([C:21]1[C:22]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:31])#[N:30]
Reactant: [H][H]
Reactant: N#Cc1cc2c3c(cccc3c1N1CCCCC1)C(=O)N(OCc1ccccc1)C2=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: N#Cc1cc2c3c(cccc3c1N1CCCCC1)C(=O)N(O)C2=O
Yield: 45.9 %

Procedure:
A mixture of 2-benzyloxy-5-cyano-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.16 g, 0.40 mmol, from Example D2) and 5% Pd/BaSO4 (0.05 g) in THF (75 mL) was shaken in an atmosphere of hydrogen at 50 psi at ambient temperature for 86 hours with an additional 0.05 g of 5% Pd/BaSO4 being added after 70 hours. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure. The residue was chromatographed on silica using chloroform/methanol (10:1) to give 0.059 g of the title compound, mp>250° C.
Reaction SMILES: NCC(O)=O.[CH2:6]([OH:17])[C@H:7]([OH:16])[C@H:8]1[O:13][C:11](=[O:12])[C@@H:10]([OH:14])[C@@H:9]1[OH:15].O=O>C(O)C>[O:12]=[C:11]1[O:13][C@H:8]([C@H:7]([CH2:6][OH:17])[OH:16])[C:9]([OH:15])=[C:10]1[OH:14]
Reactant: O=C1O[C@H]([C@@H](O)CO)[C@@H](O)[C@@H]1O
Agent: NCC(=O)O
Agent: O=O
Solvent: CCO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 20 h

Procedure:
In a similar airlift tower experiment a high cell density fermentation was performed. In this instance a 24 hour wet cell paste of C. norvegensis KCC MF-42 was dispersed in the 4.0 liter tower at a level of 100 gL-1 in SM-l medium containing 0.7% glycine and 0.7% L-Galactono-gamma-lactone. Ethanol was supplied continuously at a level (0.1-0.3%) neither limiting or inhibitory to yeast growth or productivity. Oxygen-enriched aeration was supplied to the fermentor at 1:1 oxygen-air ratio. Total mixed gas volume was 1.7 V/V/min. Under these conditions a dissolved oxygen saturation level of 30% was maintained in the upper section of the tower. After 20 hours of fermentation, L-ascorbic acid was produced at a level of 1.44 gL-1.