Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH:22]([CH3:24])[CH3:23])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH:25]=[O:26])=[CH:11][N:10]=1)=[O:8])[CH3:2].O.P([O-])(O)(O)=[O:32].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH:22]([CH3:24])[CH3:23])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:25]([OH:32])=[O:26])=[CH:11][N:10]=1)=[O:8])[CH3:2]
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OC(C)C)c(OC)cc23)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC(C)C)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.7 %

Procedure:
To a stirred solution of 1-(3-ethoxy-benzoyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde (31 mg, 0.079 mmol) in t-butanol (1 mL) and water (1 mL) solution was added sodium dihydrogenphosphate monohydrate (44 mg, 0.32 mmol), 2-methyl-2-butene (0.053 mL, 0.48 mmol) and sodium chlorite (43 mg, 0.48 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate to afford 1-(3-ethoxy-benzoyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carboxylic acid (8 mg, 23% yield) as a light yellow solid. HR-MS m/e calcd for C23H23N1O6 (M−H+) 410.1598, found 410.1601; 1H NMR (300 MHz) compatible.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[C:7]([CH:20]([O:26][CH3:27])[C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23])[CH:6]=1)=O.CC(C1C=C(CO)C=CC=1C1C=C(OC)C=CC=1F)(C)C>>[F:19][C:12]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([CH2:3][OH:2])=[CH:6][C:7]=1[CH:20]([O:26][CH3:27])[C:21]([CH3:24])([CH3:25])[CH:22]=[CH2:23]
Reactant: C=CC(C)(C)C(OC)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Agent: COc1ccc(F)c(-c2ccc(CO)cc2C(C)(C)C)c1
Product: C=CC(C)(C)C(OC)c1cc(CO)ccc1-c1cc(OC)ccc1F

Procedure:
Compound 66.41F was synthesized from 66.41E by a method analogous to that used to prepare compound 8.9 from 8.8. MS ESI m/e: 345.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[N:24]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:31]1[CH2:30][CH2:29][CH:28]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH2:33][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1cnn(C2CCNCC2)c1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC(n2cccn2)CC1
Yield: 51.6 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.215 g, 0.625 mmol) obtained in Example 22, step 3 and 4-(1H-pyrazol-1-yl)piperidine hydrochloride (WO2004/094371, 0.129 g, 0.687 mmol), the title compound (0.155 g, 52%) was obtained.
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:39]=[N:40][N:41](C3CCCCO3)[CH:42]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:49][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:42]=[N:41][NH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CC(F)(F)CC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CC(F)(F)CC[C@@H]1c1cn[nH]c1
Yield: 84 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the 4-({(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (0.20 g, 0.28 mmol) prepared in Example 127a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL), dichloromethane (2.0 mL) and methanol (2.0 mL), to yield the title compound (0.11 g, 85%) as a colorless solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[C:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1>C(O)C.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH:5]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=CCCBr)c2ccc(OC)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(CCCBr)c2ccc(OC)cc2)cc1

Procedure:
44 g (0.127 mol) of 4-bromo-1,1-bis(4-methoxyphenyl)-butene were dissolved in 160 ml of ethanol, 2.8 g of palladium-on-charcoal (10%) were added and hydrogenation was carried out in a shaking vessel at room temperature in the course of about 2 hours. The catalyst was then filtered off with suction, the filtrate was concentrated and the crude product was purified by fractional distillation. 34.4 g of a fraction were obtained at 220°-226° C./-0.2 mm.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([CH2:11][CH2:12][O:13][CH3:14])[CH2:7][CH2:8][CH2:9][OH:10].C(Cl)(C(Cl)=O)=O.CS(C)=O.C(N(CC)CC)C.COCCC(CC=C)CO>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([CH2:11][CH2:12][O:13][CH3:14])[CH2:7][CH2:8][CH:9]=[O:10]
Reactant: COCCC(CCCO)C1OCCO1
Agent: C=CCC(CO)CCOC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCCC(CCC=O)C1OCCO1
Yield: 80.8 %

Procedure:
The alcohol 7 (6 g, 29.37 mmol), prepared according to Example 6, was oxidized using 2M (COCl)2 (18 mL, 36 mmol), dry DMSO (5.1 mL, 72 mmol) and triethyl amine (20.7 mL, 144 mmol) analogous to the oxidation of the alcohol 4, as described in example 4. Similar work up as for 5 gave the aldehyde 8 (4.8 g, 81%) as a colorless oil. IR (KBr) υmax 2939, 2880, 2735, 1719, 1451, 1391, 1111, 1038, 947 cm−1: 1HNMR (CDCl3) δ1.45-2.85 (m, 5 H), 2.54 (t, J=6.8 Hz, 2 H), 3.31 (s, 3 H), 3.43-3.46 (m, 2 H), 3.83-3.95 (m, 4 H), 2.54 (t, J=6.8 Hz, 2 H), 3.31 (s, 3 H), 3.43-3.46 (m, 2 H), 3.83-3.95 (M, 4 H), 4.77 (d, J=3.3 Hz, 1 H), 9.76 (t, J=1.5 Hz, 1 H); 13CNMR (CDCl3) δ21.51, 29.23, 37.99, 41.72, 58.42, 64.81, 64.88, 70.66, 106.26, 202.39: mass spectrum (EI), m/z (rel intensity) 210 (33), 202 (M+, 3), 201 (15), 157 (19), 144 (27), 143 (38), 141 (19), 127 (17), 126 (1), 111 (30), 109 (12), 100 (4), 99 (11), 73 (100), 59 (10), 57 (8), 55 (12), 54 (5).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:24][F:25])([CH3:23])[C:4](=[O:22])[CH:5]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[BH4-].[Na+].Cl>CO>[F:1][CH2:2][C:3]([CH2:24][F:25])([CH3:23])[CH:4]([OH:22])[CH:5]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=1
Reactant: CC(CF)(CF)C(=O)C(Oc1cccc(C(F)(F)F)c1)n1ccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(CF)(CF)C(O)C(Oc1cccc(C(F)(F)F)c1)n1ccnc1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
63.7 g (0.176 mole) of 3,3-bisfluoromethyl-1-(imidazol-1-yl)-1-(3-trifluoromethylphenoxy)-butan-2-one (obtained as described in Example 1) were dissolved in 250 ml of methanol, and 3 g (0.08 mole) of sodium borohydride were added in portions. The reaction solution was subsequently stirred for 1 hour and was then adjusted to a pH value of 3 with concentrated hydrochloric acid. After distilling off the solvent in vacuo, water was added to the residue and the mixture was extracted by shaking with methylene chloride. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. 44.5 g (70% of theory) of 3,3-bisfluoromethyl-1-(imidazol-1-yl)-1-(3-trifluoromethylphenoxy)-butan-2-ol of melting point 107°-20° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:29][CH:28]=[CH:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:29][CH:28]=[CH:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1=CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CC=CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide and 2,5-dihydropyrrole, TBTU, and triethylamine in DMSO.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1.Cl.[CH3:12]O>>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:12])=[O:9])[N:3]=1
Reactant: CO
Reactant: Cn1nc(C(=O)O)nc1N
Agent: Cl
Product: COC(=O)c1nc(N)n(C)n1

Procedure:
A stirred suspension of 5-amino-1-methyl-1H-1,2,4-triazole-3-carboxylic acid (9.10 g) in methanol (100 ml) was saturated with dry hydrogen chloride, and heated under reflux for 4.5 h. The cooled solution was partially evaporated, diluted with water (100 ml) and the pH was adjusted to pH 7 with potassium carbonate. The solution was filtered, and the filtrate partially evaporated to give the title compound as a white solid (4.60 g) m.p. 190-1; tlc System B, Rf 0.6.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:37])[CH:35]=[CH2:36].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.ClCCl>[CH3:11][C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2](/[CH:36]=[CH:35]/[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH:10]=[CH:9][CH:8]=2
Reactant: Cc1cc2c(Br)cccc2[nH]1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(/C=C/C(=O)OCc3ccccc3)cccc2[nH]1
Temperature: 140 °C

Procedure:
A mixture of 4-bromo-2-methyl-1H-indole (containing 25% of the 6-bromo isomer) (8.30 g), palladium (II) acetate (0.45 g), tri-o-tolylphosphine (1.22 g), benzyl acrylate (9.76 g) and triethylamine (8.36 ml) in acetonitrile (8 ml) was heated in an oil bath at 140° C. under an atmosphere of nitrogen for 2 hours. The mixture was cooled and partitionedbetween dichloromethane and water. The organic layer was separated, washed three times with water and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/hexane (1:1) first gave impurity followed by pure product.The product fractions were evaporated and the residue was triturated with ether to give the title compound (6.60 g), m.p. 135°-136° C.Found: C,77.98; H,6.10; N,4.71. C19H17NO2 requires: C,78.33; H,5.88; N,4.81%. Further elution with dichloromethane/hexane (4:1) gave benzyl (E)-3-(2-methyl-1H-indol-6-yl)-2-propenoate (2.0 g), m.p. 164°-165° C. Found: C,78.53; H,6.06; N,4.74. C19 H17NO2 requires: C,78.33; H,5.88; N,4.81%.
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[C:22]([C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1)(=[O:24])[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:30][CH2:29][C:28]2[CH:32]=[CH:33][C:25]([C:22](=[O:24])[NH2:23])=[CH:26][CH:27]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: NC(=O)c1ccc(CCBr)cc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccc(C(N)=O)cc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-cyano-1,1-diphenylmethyl)piperidine (0.303 g), 4-carbamoylphenethyl bromide (0.275 g--see Preparation 5), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5%). The product-containing fractions were combined and concentrated inn vacuo to give the title compound as a gum, yield 0.065 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][NH:30][CH3:31])[CH:26]=[CH:27][CH:28]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:30]([CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH3:31])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CNCc1cccc(OC)c1
Product: COc1cccc(CN(C)C(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-(3-methoxyphenyl)-N-methyl-methanamine (18.0 mg, 0.12 mmol). The title compound was obtained as a solid (18.5 mg, 38% yield). MS m/z: 484.01, 486.01 [M+H]+.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9]([OH:20])([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[Na+]>C(O)C.O>[CH3:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:9]2([OH:20])[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CCC(O)(Cc2ccc(C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(CC2(O)CCNCC2)cc1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A mixture of 4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-carboxylic acid ethylester (70.5 g, 0.25 mol) and sodium hydroxide (26 g, 0.65 mol) in ethanol (350 ml) and water (50 ml) was refluxed for 2 days. Sodium hydroxide (20 g, 0.50 mol) was added and refluxing commenced for another day before cooling to room temperature and evaporating the solvent. The residue was taken up with CH2Cl2 (700 ml) and water (1 l), the organic phase was separated and the water phase extracted with CH2Cl2. The organic phases were pooled, dried with MgSO4 and the solvent was evaporated. The residue was crystallized from n-hexane to give 4-(4-methyl-benzyl)-piperidin-4-ol (34 g, 66%) as an off-white solid, m.p. 118°-121° C. and MS: m/e=206 (M+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.OCC1CCOC1.[C:14]([OH:17])(=[O:16])[CH3:15]>O>[C:14]([O:17][CH2:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)(=[O:16])[CH3:15]
Reactant: CC1CCOC1
Reactant: CC(=O)O
Agent: OCC1CCOC1
Solvent: O
Product: CC(=O)OCC1CCOC1

Procedure:
Process for the preparation of 3-methyltetrahydrofuran (3-MeTHF) by the steps comprising (1) contacting 3-(hydroxymethyl)tetrahydrofuran (3-HOMeTHF) with acetic acid at a temperature of about 120 to 210° C. in an esterification zone using apparatus which permits water to be removed from the esterification zone to produce 3-(acetoxymethyl)tetrahydrofuran (3-AcOMETHF); (2) heating the 3-AcOMETHF in a pyrolysis zone at a temperature in the range of about 380 to 510° C. for a about 1 to 10 seconds to convert the ester compound to 3-methyleneTHF; and (3) contacting the 3-methyleneTHF with hydrogen at a temperature of 25 to 100° C. and a pressure in the range of about 1 to 50 bar absolute in the presence of a hydrogenation catalyst selected from supported catalysts comprising about 1 to 10 weight percent palladium, platinum or rhodium deposited on a catalyst support material to convert the 3-methyleneTHF to 3-MeTHF.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1.[Cl:22][C:23]1[C:28]([C:29](O)=[O:30])=[C:27]([F:32])[C:26]([NH:33][S:34]([CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)(=[O:36])=[O:35])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:22][C:23]1[C:28]([C:29]([NH:12][C:9]2[CH:10]=[C:11]3[C:3]([O:2][CH3:1])=[N:4][N:5]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[C:6]3=[N:7][CH:8]=2)=[O:30])=[C:27]([F:32])[C:26]([NH:33][S:34]([CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)(=[O:36])=[O:35])=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2nc(OC)c3cc(N)cnc32)cc1
Reactant: COc1ccc(OCCCS(=O)(=O)Nc2ccc(Cl)c(C(=O)O)c2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2nc(OC)c3cc(NC(=O)c4c(Cl)ccc(NS(=O)(=O)CCCOc5ccc(OC)cc5)c4F)cnc32)cc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A 100 mL, round-bottomed flask was charged with 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (123.0 mg, 0.43 mmol), 6-chloro-2-fluoro-3-(3-(4-methoxyphenoxy)propylsulfonamido)benzoic acid (271.1 mg, 0.65 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (124.4 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (99.4 mg, 0.65 mmol), N-ethyl-N-isopropylpropan-2-amine (83.9 mg, 0.65 mmol) and DCM (1.5 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (about 12 hours). Then the reaction mixture was partitioned between EtOAc (300 mL) and water (150 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3×150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (EtOAc/hexane from 1/4 to 1/0, v/v) to afford 6-chloro-2-fluoro-N-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(3-(4-methoxyphenoxy)propylsulfonamido)benzamide (228.3 mg, 77.14%). LRMS (APCI pos): >95% purity, 254 nm, m/e 684.1 and 686.2 (M+1).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[NH:35][C:33](=[O:34])[C@@H:32]([NH:36][C:37]([C:39]2[N:44]=[CH:43][CH:42]=[CH:41][C:40]=2[OH:45])=[O:38])[C@@H:31]([CH3:46])[O:30][C:28](=[O:29])[C@H:27]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:26][C:24](=[O:25])[C@H:23]2[N:17]([CH2:18][CH2:19][C:20]([CH2:22]2)=[O:21])[C:15](=[O:16])[CH:14]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:13]([CH3:60])[C:11](=[O:12])[C@H:10]2[N:6]([CH2:7][CH2:8][CH2:9]2)[C:4]1=[O:5].C[C@H]1[C@@H](C(C)C)OC(=O)C2N(CCC=2)C(=O)C2=COC(=N2)CC(=O)C[C@H](O)C=C(C)C=CCNC(=O)C=C1.C(O)(=O)C(C)O.C1C(C2OC(CCC(O)=O)=CC=2)=CC=C(Cl)C=1.OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH-].[Na+]>>[CH3:1][CH2:2][CH:3]1[NH:35][C:33](=[O:34])[CH:32]([NH:36][C:37]([C:39]2[N:44]=[CH:43][CH:42]=[CH:41][C:40]=2[OH:45])=[O:38])[CH:31]([CH3:46])[O:30][C:28](=[O:29])[CH:27]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:26][C:24](=[O:25])[CH:23]2[N:17]([CH2:18][CH2:19][C:20]([CH2:22]2)=[O:21])[C:15](=[O:16])[CH:14]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:13]([CH3:60])[C:11](=[O:12])[CH:10]2[N:6]([CH2:7][CH2:8][CH2:9]2)[C:4]1=[O:5]
Reactant: CC[C@H]1NC(=O)[C@@H](NC(=O)c2ncccc2O)[C@@H](C)OC(=O)[C@H](c2ccccc2)NC(=O)[C@@H]2CC(=O)CCN2C(=O)C(Cc2ccccc2)N(C)C(=O)[C@@H]2CCCN2C1=O
Agent: CC(O)C(=O)O
Agent: CC1=C[C@@H](O)CC(=O)Cc2nc(co2)C(=O)N2CCC=C2C(=O)O[C@H](C(C)C)[C@H](C)C=CC(=O)NCC=C1
Agent: CC1=C\[C@@H](O)CC(=O)Cc2nc(co2)C(=O)N2CCC=C2C(=O)O[C@H](C(C)C)[C@H](C)/C=C/C(=O)NC\C=C\1
Product: CCC1NC(=O)C(NC(=O)c2ncccc2O)C(C)OC(=O)C(c2ccccc2)NC(=O)C2CC(=O)CCN2C(=O)C(Cc2ccccc2)N(C)C(=O)C2CCCN2C1=O

Procedure:
To determine the Lactrol® dose required to prevent lactic acid formation during hydrolysate fermentation, a portion of intentionally-contaminated seed culture F1067 at EFT=19.3 hr (from Example 1) was used as a seed culture to inoculate cob hydrolysate medium (FRF13; see General Methods) (adjusted to pH 5.8, +10 mM sorbitol) at 10 vol % (final volume) containing either 0 ppm (sample F1069) or 2 ppm (sample F1071) of Lactrol®, which was then fermented at 33° C. (reduced to 30° C. at EFT=21 hr) and pH 5.8 (adjusted with 4 N NaOH).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH:13]([OH:26])[CH2:14][N:15](CC2C=CC=CC=2)[CH:16]([CH3:18])[CH3:17])=[CH:11][C:10]=1[NH:29][CH:30]=[O:31])C1C=CC=CC=1.CCOCC>C(O)C.[C].[Pd]>[CH:30]([NH:29][C:10]1[CH:11]=[C:12]([CH:27]=[CH:28][C:9]=1[OH:8])[CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:18])[CH3:17])=[O:31]
Reactant: CC(C)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)NCC(O)c1ccc(O)c(NC=O)c1

Procedure:
In 20 ml. of ethanol there was dissolved 1.4 g. of 4-benzyloxy-3-formylamino-α-(N-benzyl-N-isopropylaminomethyl)-benzyl alcohol and after adding to the solution 0.2 g. of 10% palladium carbon, the catalytic reduction was carried out at normal temperature and pressure. After 165 ml. of hydrogen was absorbed, the reaction was stopped. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and then the residue thus formed was dissolved in a small amount of ethanol. Thereafter, when a small amount of ether was added to the solution and the solution was allowed to stand, a crystalline material was formed. By recovering the crystalline material by filtration, 0.7 g. of 3-formylamino-4-hydroxy-α-(isopropylaminomethyl)benzyl alcohol was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]4=[CH:17][CH:18]=3)[NH:13][C:12](=[O:24])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]4=[CH:17][CH:18]=3)[NH:13][C:12](=[O:24])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CC(c2cccc([N+](=O)[O-])c2)c2ccc3ccccc3c2N1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Yield: 85 %

Procedure:
To a stirred suspension of 4-(3-Nitro-phenyl)-3,4-dihydro-1H-benzo[h]quinolin-2-one (1.0 g, 3.14 mmol) and 10% Pd/C (0.10 g) in ethanol (50 ml) was slowly added hydrazine hydrate (0.40 g, 12.6 mmol). The solution was refluxed for 2 hr and the catalyst separated by filtration. The filtrate was concentrated in vacuo to 20 ml and the solution stored in a refrigerator overnight. The precipitate was separated by filtration, washed with small amount of ethanol and vacuum dried to afford the product (0.77 g, 2.67 mmol).