Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=2)[CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:1]1([C:7]#[C:8][C:9]2[CH:16]=[C:13]([CH2:14][OH:15])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cncc(C#Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(C#Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-(Phenylethynyl)nicotinaldehyde (7.0 g, 33.8 mmol) in ethanol (150 mL), immersed in a room temperature bath to moderate any potential exotherm, was added sodium borohydride (0.639 g, 16.9 mmol) in one portion. After 30 min at room temperature, the reaction was cooled to 0° C. and quenched by the cautious addition of saturated ammonium chloride. The reaction was concentrated and partitioned between water and ether. The aqueous was extracted with ether (2×). The organics were washed with brine, dried over magnesium sulfate, and concentrated to give a faint yellow solid. Material was used without purification. 1H NMR (CDCl3) δ: 8.39-8.81 (m, 2H), 7.88 (s, 1H), 7.51-7.61 (m, 2H), 7.34-7.44 (m, 3H), 4.77 (s, 2H), 3.21 (br. s., 1H). 13C NMR (CDCl3) δ: 151.1, 147.1, 137.3, 131.8, 129.0, 128.6, 122.5, 93.0, 85.9, 62.3. Mass spec.: 210.1 (MH)+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[C:6]([OH:9])(=[S:8])[CH3:7]>C(O)C.C(N(CC)CC)C>[C:6]([S:8]/[CH:3]=[CH:2]\[C:1]([OH:5])=[O:4])(=[O:9])[CH3:7]
Reactant: CC(O)=S
Reactant: C#CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)S/C=C\C(=O)O
Reaction time: 0.08 h
Yield: 117.9 %

Procedure:
To a stirred, cooled (0° C.) solution of 1.0 ml (0.01625 mol) of propiolic acid in 12 ml of absolute ethanol under nitrogen was added 0.22 ml (0.0016 mol) of triethylamine. After 5 min, 1.45 ml (0.0203 mol) of thioacetic acid was added. After 20 h at 0° C. the reaction mixture was stripped of solvents to give 2.8 g of cis-3-(acetylthio)propenoic acid as a waxy solid. This product was used in the next step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[F:21][CH2:22][C:23](OCC)=[O:24]>O1CCCC1.CCOCC>[F:21][CH2:22][C:23](=[O:24])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CCOC(=O)CF
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CC(=O)CF
Temperature: -78 °C

Procedure:
A solution containing 12.6 g (125 mmol) of diisopropylamine in 90 ml of dry tetrahydrofuran was cooled to -78° C. and 52.4 ml of 2.5 M n-butyllithium (131 mmol) was added. A solution of 14.5 g (125 mmol) of t-butyl acetate in 10 ml of tetrahydrofuran was then added dropwise over a 30 min period with stirring and allowed to react for another 30 min at -78° C. A solution of 6.00 g (56.6 mmol) of ethyl fluoroacetate in tetrahydrofuran was added dropwise with stirring to the resultant pale yellow solution and the mixture allowed to react for another 30 min at -78° C. and then allowed to stir and warm to ambient temperature over one hour. The resulting pale yellow solution was diluted with 250 ml of ether and the ethereal solution was extracted with 250 ml of 1 N HCl, 250 ml of water, and 250 ml of saturated aqueous sodium bicarbonate. The solution was then dried over magnesium sulfate and distilled at atmospheric pressure to remove the solvents. The residue was fractionally distilled under reduced pressure from a based-washed and oven-dried flask containing a few potassium bicarbonate crystals to obtain 7.00 g (70 percent of theory) of the desired product as a colorless oil boiling at 72°-74° C. at 10 torr. The proton and fluorine nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(Oc2ccccc2)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-3-phenoxybenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.12 min.; [M+H]+: 418.79 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](CC3C=C(OCC)C(F)=C(OCC)C=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1.[CH2:36]([O:38][C:39]1[CH:44]=[C:43]([CH:45]=O)[CH:42]=[C:41]([O:47][CH2:48][CH3:49])[C:40]=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)[CH3:37].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:45][C:43]3[CH:44]=[C:39]([O:38][CH2:36][CH3:37])[C:40]([C:50]4[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=4)=[C:41]([O:47][CH2:48][CH3:49])[CH:42]=3)[CH2:14][CH2:15]2)=[O:8])[CH:5]=1
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), 5-methoxy-N-piperidin-4-yl-isophthalamic acid methyl ester (example 143) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 565.3 (MH+).
Reaction SMILES: N[C:2]1[C:11]([CH3:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:14][B-](F)(F)F.N#[O+].C1C(Cl)=CC=C(Cl)C=1>C(Cl)Cl>[F:14][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)cc(C)c1N
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: Clc1ccc(Cl)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(F)cc(C)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (E3) (1.0 eq.) in dry DCM (0.4 M) at 0° C. was added nitrosonium tetrafluoroborate (1.3 eq.) portionwise. After 1 h at 0° C. dry dichlorobenzene (120 eq.) was added and the reaction was slowly heated to 160° C. while DCM was distilled off. After 3 hrs, the mixture was cooled to RT, EtOAc was added and the organic phase was washed with brine (2×). After drying over MgSO4, the solvents were removed under reduced pressure. The crude was purified by flash chromatography using 1-10% EtOAc/petroleum ether to yield (E4) as a yellow oil. 1H NMR (400 MHz, CDCl3, 300K) δ 7.42 (1H, m), 7.06 (1H, m), 3.92 (3H, s), 2.30 (3H, d, J=2.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([C:19]#[CH:20])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: C#Cc1cnc2c(c1)C(=O)N(C)c1ccc(Cl)nc1N2CC
Product: CCN1c2ncc(CCc3ccnc(C(=O)O)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 34.9 %

Procedure:
By a procedure analogous to that described in Example 51b, 2-chloro-5,11-dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.83 g, 2.64 mmol) was coupled with 4-bromopicolinic acid (prepared by potassium permanganate oxidation of 4-bromo-2-picoline) (0.53 g, 2.62 mmol). The product was hydrogenated according to the procedure described in Example 3b to provide 0.4 g of the title compound as a mixture containing the corresponding des-chloro analog.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@H:3]([OH:16])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:6]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>>[C:20](=[O:21])([O:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[O:16][C@H:3]([CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:6]1)[C:2]([CH3:18])([CH3:17])[CH3:1]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[C@H](O)Cn1ccc(-c2cccnc2)n1
Product: CC(C)(C)[C@@H](Cn1ccc(-c2cccnc2)n1)OC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
(2S)-3,3-Dimethyl-1-[3-(3-pyridinyl)-1H-pyrazol-1-yl]-2-butanol was treated with p-nitrophenyl chloroformate as previously described in example 1g to provide the title compound as a solid foam. 1H-NMR (DMSO-d6): δ 8.97 (s, 1H), 8.46 (d, J=4 Hz, 1H), 8.13 (d, J=9 Hz, 2H), 8.10 (d, J=8 Hz, 1H), 7.9 (d, J=2 Hz, 1H), 7.38 (dd, J=7 Hz, J=4 Hz, 1H), 7.22 (d, J=9 Hz, 2H), 6.83 (d, J=2 Hz, 1H), 4.90 (d, J=9 Hz, 1H), 4.62 (d, J=14 Hz, 1H), 4.35 (dd, J=14 Hz, J=9 Hz, 1H), 1.03 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9]O.S(Cl)([Cl:13])=O>>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH2:9][Cl:13])=[CH:4][N:5]=1
Reactant: OCc1cnc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Product: ClCc1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(4,6-Dichloro-pyridin-3-yl)-methanol (2.21 g, 12.41 mmol) is cooled under an atmosphere of argon to 0° C. Thionyl chloride (8 ml) is carefully added. After 5 minutes at 0° C., the solution is heated to reflux. After 10 minutes, TLC analysis indicated complete conversion of the starting material. After cooling to RT, excess thionyl chloride is removed via a membrane pump. The remaining oil is dissolved in EtOAc. The solution is poured into a concentrated aqueous solution of NaHCO3. The organic layer is separated and washed twice with a concentrated aqueous solution of NaCl. After drying over Na2SO4, the organic solvent is removed to afford the title compound of adequate purity for immediate further use. 1H NMR (CDCl3, 400 MHz): δ 4.65 (s, 2H), 7.42 (s, 1H), 8.44 (s,1H). ES+−MS: 195, 197, 199 (3 Cl) [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Br)cc2)C1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3CCOCC3)cc2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate I, 680 mg, 2.01 mmol) in anhydrous toluene (20 mL) were added Pd2(dba)3 (4.6 mg, 0.005 mmol), BINAP (9.4 mg, 0.015 mmol), sodium tert-butoxide (232 mg, 2.41 mmol) and morpholine (0.2 mL, 2.21 mmol) at r.t. and reaction mixture was stirred at 90° C. for 4 h. Reaction mixture was then concentrated and crude product was purified by column chromatography (silica gel, 1:9 EtOAc:Pet. ether) to afford the title compound as white solid (456 mg, 66%).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[N:22]1([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH:26]=[N:25][N:24]=[N:23]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:28][CH:29]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1ccc(-n2cnnn2)cc1
Product: O=C(c1ccc(-n2cnnn2)cc1)N(C1CC1)C1CCN(c2ncc(C(F)(F)F)cc2F)CC1

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 4-tetrazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.46 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[N:60]1([C:66]([O:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[O:67])[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[C:13]([O:12][C:11]([NH:10][C@@H:8]([C:4]1[CH:3]=[C:2]([N:63]2[CH2:62][CH2:61][N:60]([C:66]([O:68][CH2:69][C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[O:67])[CH2:65][CH2:64]2)[CH:7]=[CH:6][CH:5]=1)[CH3:9])=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
To a suspension of Intermediate 10A (50 mg, 0.17 mmol) and Pd2(dba)3 (15 mg, 0.017 mmol) in toluene (2 mL) was added Xantphos (29 mg, 0.050 mmol), benzyl piperazine-1-carboxylate (37 mg, 0.17 mmol), followed by sodium tert-butoxide (48 mg, 0.50 mmol). The reaction mixture was stirred at 70° C. for 16 h, and then filtered. The filtrate was concentrated and purified by flash chromatography using a 15 min gradient from 0 to 100% EtOAc in hexanes to give Intermediate 10B (70 mg, 0.16 mmol, 96% yield). LC-MS (ESI) m/z 440.1 (M+H), RT=2.27 min (Method B).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:44]([N+:48]1[N:52]=[C:51]([CH3:53])[S:50][C:49]=1[CH3:54])[CH2:45][CH2:46][CH3:47]>>[CH2:44]([N:48]1[N:52]=[C:51]([CH3:53])[S:50]/[C:49]/1=[CH:54]\[C:7]([CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:9])[CH2:45][CH2:46][CH3:47]
Reactant: O=C(O)CC1CCCC1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-cyclopentylacetic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.06-1.16 (m, 2 H) 1.24-1.34 (m, 2 H) 1.43-1.54 (m, 2 H) 1.53-1.61 (m, 2 H) 1.63-1.73 (m, 4 H) 2.14-2.23 (m, 1 H) 2.30-2.34 (m, 2 H) 2.39-2.43 (m, 3 H) 4.03 (t, 2 H) 5.90 (s, 1 H); MS (ESI) m/z 281 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][S:7][CH3:8])[C:3]#[N:4].S(=O)(=O)(O)[OH:10]>>[OH:1][CH:2]([CH2:5][CH2:6][S:7][CH3:8])[C:3]([NH2:4])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: CSCCC(O)C#N
Product: CSCCC(O)C(N)=O

Procedure:
A process as set forth in claim 1 wherein 2-hydroxy-4-methylthiobutanenitrile is hydrolyzed in the presence of sulfuric acid to produce an intermediate hydrolyzate comprising 2-hydroxy-4-(methylthio)butanamide; and
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17](=[O:33])[C:18]4[C:23]([F:24])=[CH:22][CH:21]=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:19]=4[F:32])[CH:14]=3)[N:9](CC3C=CC(OC)=CC=3)[N:8]=2)[CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[CH:1]1([CH2:5][O:6][C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17](=[O:33])[C:18]4[C:23]([F:24])=[CH:22][CH:21]=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[C:19]=4[F:32])[CH:14]=3)[NH:9][N:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(OCC2CCC2)nn3Cc2ccc(OC)cc2)c1F
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(OCC4CCC4)c3c2)c1F
Temperature: 50 °C
Yield: 22.3 %

Procedure:
N-(3-(Cyclobutylmethoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.017 g, 0.028 mmol) was dissolved in TFA (3 mL) and warmed to 50° C. for 16 hours. The mixture was then heated to 70° C. for 3 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in DCM (10 mL), washed with saturated sodium bicarbonate solution (2×), dried over sodium sulfate and concentrated under reduced pressure. Preparative TLC (2×0.5 mm plates, 7% MeOH/DCM) afforded N-(3-(cyclobutylmethoxy)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (3 mg, 22%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 8.67-8.62 (m, 1H), 8.56-8.52 (m, 1H), 7.68-7.62 (m, 1H), 7.17-7.10 (m, 1H), 4.39-4.33 (m, 2H), 3.15-3.08 (m, 2H), 2.93-2.82 (m, 1H), 2.22-2.13 (m, 2H), 2.04-1.82 (m, 6H), 1.10-1.02 (m, 3H); m/z (APCI-pos) M+1=480.1.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[Cl:10][C:11]([Cl:16])(Cl)[C:12](Cl)=[O:13].P(Cl)(Cl)(Cl)=O>C(OCC)C.[Cu].[Zn]>[CH2:1]([CH:2]1[CH2:3][C:12](=[O:13])[C:11]1([Cl:16])[Cl:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C1CC(Cc2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To a room temperature mixture containing allylbenzene (1.84 g, 15.6 mmol), zinc-copper couple (5.1 g, 78 mmol) and diethylether (60 ml) was added dropwise a solution of trichloroacetylchloride (2.96 ml, 26.5 mmol) and phosphorus oxychloride (2.46 ml, 26.5 mmol) in diethylether (20 ml). The reaction mixture was stirred at room temperature for 1 hour, filtered and the filtrate was partially concentrated. The residue was neutralized with saturated NaHCO3. The aqueous phase was extracted with diethylether. The combined organic phases were washed successively with H2O and brine, dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (hexane) to provide (RS)-3-benzyl-2,2-dichlorocyclobutanone (0.71 g, 20%) as a yellow oil, MS: m/e=228.1 (M-H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: BrCCCCBr
Reactant: COc1ccc2[nH]ccc2c1
Product: COc1ccc2c(ccn2CCCCBr)c1

Procedure:
The procedure is as for Example 39 using as substrate 5-methoxy-1H-indole and 1,4-dibromobutane.
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=1[C@@H:23]([CH2:29][CH:30]([F:32])[F:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])C)=O)C1C=CC=CC=1.Cl>CO.[Pd]>[NH2:20][C:18]1[CH:17]=[CH:16][C:15]([C@@H:23]([CH2:29][CH:30]([F:31])[F:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14]([CH2:13][NH:11][CH3:9])[CH:19]=1
Reactant: CCOC(=O)[C@H](CC(F)F)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@H](CC(F)F)c1ccc(N)cc1CNC
Reaction time: 12 h
Yield: 101.6 %

Procedure:
10D (115 mg, 0.255 mmol) was dissolved in MeOH (5 mL) containing HCl (93 mg, 2.55 mmol). 10% Pd/C was added. The reaction mixture was stirred under a hydrogen balloon for 12 h. Pd/C was removed by filtration and the filtrate was concentrated under reduced pressure to give 10E (93 mg, 0.259 mmol, 101% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=3[NH:12][C:13](=[O:27])[CH:14]([NH:16]C(=O)OCC3C=CC=CC=3)[N:15]=2)=[CH:5][CH:4]=1.Br.CCOCC>C(O)(=O)C>[NH2:16][CH:14]1[C:13](=[O:27])[NH:12][C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=2[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:15]1
Reactant: COc1ccc(C2=NC(NC(=O)OCc3ccccc3)C(=O)Nc3ccccc32)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(C2=NC(N)C(=O)Nc3ccccc32)cc1
Temperature: 70 °C
Yield: 89.8 %

Procedure:
Intermediate 6B (1000 mg, 2.407 mmol) was treated with 33% HBr in acetic acid (5 mL) to give a suspension. The reaction mixture was then heated to 70° C. for 3 hrs with stirring. The reaction mixture was then poured into ether (100 mL). The resulting solid was filtered and then partitioned between DCM (100 mL)/saturated NaHCO3 (100 mL). The aqueous phase was back extracted with DCM (3×100 mL). The combined organic phases were dried with MgSO4, filtered and concentrated to provided Intermediate 6C (0.608 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 10.61 (br. s., 1H), 7.62-7.53 (m, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.34-7.23 (m, 2H), 7.23-7.17 (m, 1H), 6.99 (d, J=9.0 Hz, 2H), 4.20 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH3:22][O:23][CH:24]([CH3:27])[CH2:25][NH2:26].C(#N)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:26][CH2:25][CH:24]([O:23][CH3:22])[CH3:27]
Reactant: COC(C)CN
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCO
Solvent: CC#N
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCC(C)OC)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 5 g of 2-methoxypropyl amine in 100 ml of ethanol and worked up. Colorless crystalline solid substance, melting point: 148° C. (acetonitrile/active charcoal).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:12].C(=O)(O)[O-].[Na+].[C:18](Cl)(Cl)=[S:19]>ClCCl.O>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]=[C:18]=[S:19]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1c(N=C=S)cccc1C(F)(F)F
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a two phase solution of 2-fluoro-3-trifluoromethyl-phenylamine (2 g, 11.17 mmole) in dichloromethane (40 ml) and sodium bicarbonate (6.57 g, 78.19 mmole) in water (30 ml) at 0° C. was added dropwise a solution of thiophosgene (1.28 g, 11.17 mmole) in dichloromethane (10 ml). After 2 hrs, the organic layer was separated, washed sequentially with 1M NaHCO3, brine and water. The organic layer was dried over Na2SO4, filtered and concentrated to yield 2.2 g (91%) of product as a viscous liquid. MS (ESI+) m/z 221 (M+H)+.