Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]2=[O:19])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]([N+:21]([O-])=O)=[CH:7][CH:8]=2)[N:3]=1>C1CCCCC=1.CN(C=O)C.[OH-].[OH-].[Pd+2]>[NH2:21][C:6]1[CH:5]=[C:4]2[C:9]([C:10](=[O:20])[N:11]([CH:12]3[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]3=[O:19])[C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1nc2cc([N+](=O)[O-])ccc2c(=O)n1C1CCC(=O)NC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CN(C)C=O
Product: Cc1nc2cc(N)ccc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 125 °C
Yield: 82.5 %

Procedure:
A suspension of 3-(2-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (4.8 g, 13 mmol) and 20% Pd(OH)2/C (1.0 g) in cyclohexene (15 mL) and DMF (60 mL) was heated in a 125° C. oil bath overnight. The suspension was filtered thru a pad of Celite, and washed with DMF (30 mL). To the filtrate, was added water (150 mL) to give a suspension. The suspension was filtered and washed with water (50 mL) to give 3-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (3.07 g, 71% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 5/95 grad 95/5 in 5 min CH3CN/0.1% H3PO4, 4.08 min (97.3%) [sample was dissolved in 0.1% H3PO4]; mp: 305-307° C.; 1H NMR (DMSO-d6) δ 2.05-2.16 (m, 1H, CHH), 2.53 (s, 3H, CH3), 2.58-2.69 (m, 2H, 2CHH), 2.75-2.86 (m, 1H, CHH), 5.10 (dd, J=6, 11 Hz, 1H, NCH), 6.11 (brs, 2H, NH2), 6.54 (d, J=2 Hz, 1H, Ar), 6.68 (dd, J=2, 8 Hz, 1H, Ar), 10.93 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.36, 23.43, 30.63, 55.97, 106.12, 109.17, 114.70, 127.28, 148.95, 154.42, 154.61, 159.85, 169.87, 172.67; LCMS: MH=287; Anal Calcd for C14H14N4O3: C, 58.74; H, 4.93; N, 19.57. Found: C, 58.60; H, 4.83; N, 19.40.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]3([CH2:22][CH2:21][CH2:20][CH2:19]3)[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.CCO.[BH3-]C#N.[Na+].C(O)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[CH:11]([OH:18])[C:10]3([CH2:22][CH2:21][CH2:20][CH2:19]3)[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccnc2N(c2cccc(Cl)c2)C(=O)C12CCCC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C1N(c2cccc(Cl)c2)c2ncccc2C(O)C12CCCC2
Temperature: 25 °C

Procedure:
To a solution of 2.2 g (6.73 mmol.) of 1'-(3-chlorophenyl)-spiro[cyclopentane-1,3'-[1,8]-naphthyridin]-2',4'-(1'H)dione in 176 mL of (1:1) THF: EtOH (abs.) was added 2.54 g (40 mmol.) of NaBH3CN and 3.0 mL of acetic acid. The solution was stirred at room temperature. An additional 0.2 g (3.2 mmol.) of NaBH3CN and 0.3 mL of acetic acid were added on the fourth day. After 9 days the reaction was stopped by slow addition of 10 mL of water. After concentration, the residue was purified by column chromatography, eluting with CHCl3 -CH3OH(95:5) to yield a colorless solid, 1.82 g. (5.53 mmol. 82%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13]>CCOCC>[C:10]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: Cc1cccc(C)c1N
Reactant: CCCC(=O)Cl
Solvent: CCOCC
Product: CCCC(=O)Nc1c(C)cccc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 200 g. of 2,6-dimethylaniline in 2 l. of ether is cooled in an ice bath and to this 88 g. of butyryl chloride in 150 ml. of ether is added dropwise (over 21/2 hours). A white precipitate forms and the reaction mixture is allowed to stir at 0° C. for 1 hour longer and then 15 hours at room temperature. The reaction mixture is then evaporated in vacuo and the white solid residue is slurried in 1 l. of water, filtered and washed with water and dried to obtain N-butyryl-2,6-dimethylaniline (m.p. 134°-6° C.).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[O:16][CH3:17].Cl.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:27])[CH2:22][CH2:21]1.CN1CCOCC1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO.O>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:27])[C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH2:22][CH2:21]2)=[O:13])=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Reactant: COc1cc(C(=O)O)ccc1N1CCCS1(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCC(C(=O)c3ccc(C)cc3)CC2)ccc1N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-3-methoxybenzoic acid (285 mg) described in Preparation Example 21, (piperidin-4-yl) (p-tolyl)methanone hydrochloride (252 mg) and N-methylmorpholine (0.12 mL) was dissolved in a solution of methanol (3 mL) and water (2 mL), 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (349 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (344 mg).
Reaction SMILES: [F:1][CH:2]([F:19])/[CH:3]=[CH:4]/[C:5]1([OH:18])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1>Cl.O1CCOCC1>[F:19][CH:2]([F:1])/[CH:3]=[CH:4]/[C:5]1([OH:18])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(/C=C/C(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: OC1(/C=C/C(F)F)CCNCC1
Yield: 157.5 %

Procedure:
A solution of (E)-tert-butyl 4-(3,3-difluoroprop-1-enyl)-4-hydroxypiperidine-1-carboxylate (38C) (293 mg, 1.075 mmol) in 5 mL of 3.5 N HCl in dioxane was stirred at r.t. for 30 min. The reaction mixture was concentrated in vacuo to give 300 mg of the title product as a yellow liquid which was used in the next step directly.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:5].[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[CH2:16]([O:23][C:24](=[O:25])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([C:34](=[O:35])[NH:2][CH2:3][C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=2)[CH2:30][CH2:29]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NCC1CCC(C(=O)O)CC1)OCc1ccccc1
Reactant: NCC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC1CCC(C(=O)NCC(=O)c2cccc(C(F)(F)F)c2)CC1)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 2-Amino-1-(3-trifluoromethyl-phenyl)-ethanone hydrochloride (3.4 g, 0.0144 mol (prepared according to the procedure of Leclerc and Bizec (1980) J. Med. Chem. 23:783–744) and 4-(Benzyloxycarbonylamino-methyl)-cyclohexanecarboxylic acid (4.2 g, 0.0144 mol; for a preparation of this reagent see e.g., Svahn et. al. (1986) J. Med. Chem. 29:448–453) in DMF, Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 6.4 g, 0.0144 mol) was added, followed by triethylamine (4.0 mL, 0.0289 mol). The reaction was stirred overnight and then poured into water to produce a thick precipitate. The solid was collected on a sintered glass funnel and washed consecutively with H2O, 3N HCl (2×), H2O, NaHCO3 solution (2×) and H2O. The filter cake was air dried, added to a 500 mL round bottom flask with toluene and concentrated under reduced pressure. Additional toluene (200 mL) was added and the mixture was concentrated again under reduced pressure to yield {4-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-cyclohexylmethyl}-carbamic acid benzyl ester as a solid. 1H NMR (DMSO-d6): δ0.8–0.93 (m, 2H), 1.2–1.37 (m, 3H), 1.71 (br s, 4H), 2.14 (t, 1H), 2.84 (br s, 2H), 4.57 (br s, 2H), 4.99 (s, 2H), 7.2–7.38 (m, 5H), 7.77(t, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.14–8.26 (m, 3H). MS 477 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33]C(C)(C)C)[C:28]=3O[SiH](C)C)=[CH:22][C:21]=2[Cl:42])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[CH:22][C:21]=2[Cl:42])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[SiH](C)Oc1c(OC(C)(C)C)cccc1Sc1ccc(CCCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CCCc2ccc(Sc3cccc(O)c3)cc2Cl)COC(C)(C)OC1
Reaction time: 0.17 h
Yield: 102.8 %

Procedure:
To a solution of the compound of Example 33 (1.10 g) in THF (20 mL), a 1 mol/L solution of tetrabutylammonium fluoride in THF (5 mL) was added. After 10 minutes, the reaction mixture was poured into water and was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain the desired product (900 mg) as a colorless powder.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9]([OH:24])(=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C(N)CCC[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>>[CH2:7]([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35].[C:9]([OH:24])(=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: NCCCCCCN
Reactant: NCCCCCCCCCCN
Agent: O=C(O)CCCCCCCCCCC(=O)O
Product: NCCCCCCCCCCCCN

Procedure:
PA612 is prepared in a known manner by polycondensation of an equivalent mixture of hexamethylenediamine and 1,12-dodecanedioic acid. PA1012 is prepared by polycondensation of an equivalent mixture of 1,10-decanediamine and 1,12-dodecanedioic acid, while PA1212 is obtained in the same manner from 1,12-dodecanediamine and 1,12-dodecanedioic acid.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.ClCCl>CO.ClCCl>[F:34][C:25]1[CH:26]=[C:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=[CH:29][C:24]=1[O:23][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]3)[N:15]=[CH:16][C:17]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)O)CC2)c(F)c1
Yield: 103.8 %

Procedure:
A mixture of 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 60; 520 mg, 1.06 mmol) and 20% trifluoroacetic acid/dichloromethane (12 mL) was stirred at room temperature until tlc (6% methanol/dichloromethane) indicated that the starting material had completely reacted. The solvent was evaporated, ether (5 mL) was added, and the mixture was evaporated to give a white semi-solid which was held under vacuum, then triturated with ether, and held under high vacuum to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid (479 mg, 90%) as a white powder. A mixture of 40 mg of this powder (0.08 mmol) and diisopropylethylamine (42 μL) in anhydrous dichloromethane (1 mL) was cooled to 0° C. and a solution of cyclopentyl chloroformate (Waterstone Technology, LLC, Carmel, Ind., USA; 18 mg, 0.12 mmol) in dichloromethane (250 μL) was added dropwise. The mixture was stirred at room temperature for 30 min. Water (3 mL) was added. The layers were separated and the organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, co-evaporated with ether and purified on a Silicycle 4 g column eluting with 0-10% methanol/dichloromethane to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester (27 mg, 68%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[C:15]([NH:21][C:22](=[O:28])[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[N:16][CH:17]=[C:18]([CH3:20])[N:19]=1>>[Cl:1][C:2]1[C:7]([S:8]([N:21]([C:22]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:28])[C:15]2[C:14]([O:13][CH3:12])=[N:19][C:18]([CH3:20])=[CH:17][N:16]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1nc(C)cnc1NC(=O)OCC(C)C
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl

Procedure:
reaction of 2-chloropyridine-3-sulfonyl chloride with isobutyl N-(3-methoxy-5-methylpyrazin-2-yl)carbamate in the presence of an alkali metal hydride in an inert solvent to give 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide;
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-])=O)=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:2].[ClH:16].C(O)(C)C>CO>[ClH:16].[ClH:16].[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:2]
Reactant: CCC1Cc2ccc([N+](=O)[O-])cc2CN1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CCC1Cc2ccc(N)cc2CN1
Reaction time: 1 h

Procedure:
To a pressure bottle charged with (+)-3-ethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (3.5 g) dissolved in methanol (100 ml) and saturated isopropanol-HCl (20 ml) was added 10% Pd--C (250 mg), and the reaction was hydrogenated for 1 h. The catalyst was removed by filtration and the solvent evaporated to give (+)-3-ethyl-1,2,3,4-tetrahydroisoquinolin-7-amine dihydrochloride (3.4 g), m.p. 199-200° C., [α]D +68.4° (c 0.976, methanol).
Reaction SMILES: N12CCCCC1C=NCCC2.[N+:12]([CH3:15])([O-:14])=[O:13].[C:16]([O:21][CH3:22])(=[O:20])/[CH:17]=[CH:18]/[CH3:19]>CO>[CH3:19][CH:18]([CH2:15][N+:12]([O-:14])=[O:13])[CH2:17][C:16]([O:21][CH3:22])=[O:20]
Reactant: C/C=C/C(=O)OC
Reactant: C[N+](=O)[O-]
Agent: C1=NCCCN2CCCCC12
Solvent: CO
Product: COC(=O)CC(C)C[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 144 h
Yield: 66.2 %

Procedure:
1,5-Diazabicyclo[5,4,0]-undec-5-ene (6 ml) is added to a solution of nitromethane (91.5 g) in methanol (500 ml). The resulting mixture is heated to 60° C. and methyl crotonate (100 g, lm) is added under nitrogen. The mixture is then stirred for 6 days at 60° after which it is cooled to room temperature and most of the methanol is removed in vacuo. The residue is treated with ether (500 ml) and washed with 2 N hydrochloric acid (250 ml) and water (250 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo to give crude product. The crude product is purified by column chromatography on silica gel (500 g, ethyl acetate/hexane 2:98) to give methyl 3-methyl-4-nitrobutanoate (106.6 g, 66%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.C(=O)(OC)[O:16][C:17]1[CH:22]=[C:21]([NH2:23])[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][C:18]=1[C:28]([CH3:31])([CH3:30])[CH3:29].CC1OCCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1.C[O-].[Na+].CO>>[C:24]([C:20]1[CH:19]=[C:18]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:17]([OH:16])=[CH:22][C:21]=1[NH:23][C:12]([C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:14])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)Oc1cc(N)c(C(C)(C)C)cc1C(C)(C)C
Reactant: O=C(O)c1c[nH]c2ccccc2c1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C)c(NC(=O)c2c[nH]c3ccccc3c2=O)cc1O
Reaction time: 8 h

Procedure:
4-Oxo-1,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P® 50% solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5+/−5.0° C. and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20° C.+/−5° C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times and 2-MeTHF (16.5 vol) was charged to the reactor. This solution was charged with 30% w/w NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred at 25.0° C.+/−5.0° C. for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1.2 N HCl/H2O (10.0 vol), and washed with 0.1 N HCl/H2O (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17](O)=O)[C:9]=2[F:20])[CH:5]=[CH:6][CH:7]=1.[NH2:21][NH:22][C:23]([NH2:25])=[S:24].O>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[S:24][C:23]([NH2:25])=[N:22][N:21]=3)[C:9]=2[F:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)O)c(F)c1-c1cccc(Cl)c1
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(Cc2nnc(N)s2)c(F)c1-c1cccc(Cl)c1
Temperature: 120 °C
Yield: 39 %

Procedure:
A mixture of (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid (I-79) (0.998 mmol, 1.0 eq.) and thiosemicarbazide (2.99 mmol; 3 eq.) in excess phosphorous oxychloride was heated to 120° C. for 45 minutes, and allowed to cool to room temperature. The resultant mixture was added to water, and extracted with 2 portions of ethyl acetate. The organics were washed with brine, and dried over magnesium sulfate. The residue was purified via flash chromatography on silica gel using 5% (1N NH3 in MeOH) in dichloromethane as eluent to afford the desired product (P-333) in 39% yield.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=1.CS([Cl:23])(=O)=O.C(N(CC)CC)C.CCOC(C)=O.CCCCCCC>C(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47077.6 %

Procedure:
To a solution of (S)-tert-butyl 1-(4-(hydroxymethyl)phenyl)ethylcarbamate (503 mg, 2 mmol) in DCM (10 mL) was added methanesulfonyl chloride (275 mg, 2.4 mmol) and triethylamine (0.56 mL, 4 mmol). The solution was stirred for 16 h at room temperature then washed with water and brine. After separation, the organic phase was dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 80%) provided (S)-tert-butyl 1-(4-(chloromethyl)phenyl)ethylcarbamate as a white solid (254 g, 47.1% yield).
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@@H:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][O:8][C@H:9]2[C@@H:14]([NH:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(N[C@H]1CCN(Cc2ccccc2)C[C@H]1OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@H]1CCNC[C@H]1OCc1ccccc1)c1ccccc1

Procedure:
A mixture of 150 parts of cis-N-[3-(phenylmethoxy)-1-(phenylmethyl)-4-piperidinyl]benzamide and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 9 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaportated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a firs fraction of 42 parts of cis-N-[3-(phenylmethoxy)-4-piperidinyl]-benzamide. The mother-liquor was evaporated, yielding 70 parts of cis-N-[3-(phenylmethoxy)-4-piperidinyl]benzamide as an oily residue (compound 221).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:27])=[CH:21][C:22]([CH3:26])=[N:23]2)=[CH:18][CH:17]=1)=O)C>O1CCCC1>[Cl:27][C:20]1[C:19]2[C:24](=[CH:25][C:16]([CH2:14][OH:13])=[CH:17][CH:18]=2)[N:23]=[C:22]([CH3:26])[CH:21]=1
Reactant: CCOC(=O)c1ccc2c(Cl)cc(C)nc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c2ccc(CO)cc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Diisobutylaluminum hydride (1 M solution in tetrahydrofuran, 80 mL, 80 mmol) was added dropwise at 0° C. to a solution of 4-chloro-2-methyl-quinoline-7-carboxylic acid ethyl ester (4.42 g, 17.7 mmol) in tetrahydrofuran (90 mL), then after stirring 1 h at 0° C. the reaction was quenched by careful addition of methanol (4.5 mL) and 1 M aq. potassium sodium tartrate solution (135 mL). The two-phase mixture was stirred 30 min, then extracted twice with ethyl acetate. The organic phases were washed with brine, dried (MgSO4) and evaporated. Chromatography (SiO2, hexane/ethyl acetate 1:1 afforded the title compound (2.62 g, 71%). Off-white solid, EI-MS: m/e==207.2 (M+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:3].[CH3:26]N(C(OC)OC)C>CN(C=O)C>[CH3:26][O:14][C:13]1[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[C:6]2[C:10](=[CH:11][C:12]=1[O:15][CH3:16])[N:9]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH:8]=[CH:7]2
Reactant: COC(OC)N(C)C
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c(CN(C)C)c1O
Solvent: CN(C)C=O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c(CN(C)C)c1OC

Procedure:
4-[(Dimethylamino)methyl]-6-methoxy-1-(phenylsulfonyl)-1H-indol-5-ol (60 mg, 0.166 mmol; Example 184) was dissolved in DMF (2 ml) and DMF-DMA (300 μl) was added. The mixture was heated in microwave oven at 180 oC for 180 s. Solvent was evaporated and the residue purified on Gilson HPLC using 30-60% MeCN in 50 nM ammonium hydrogencarbonate buffer as eluent. Yield: 13.2 mg (21%); brown oil. MS (ESI+) for C19H22N2O4S m/z 375 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[N:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].O>CCCCCC.C1COCC1>[CH2:3]([O:10][C:12]1[C:13]([C:14]#[N:15])=[CH:16][CH:17]=[CH:18][N:19]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1cccnc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 2.89 g, 72.3 mmol) was washed with hexane (1×) and suspended in THF (50 ml). Anhydrous benzyl alcohol (8.57 g, 79.3 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes. A solution of 2-chloronicotinonitrile (10.0 g, 72.2 mmol) in THF (50 ml) was added via a syringe (exotherm). The reaction was stirred at ambient temperature for 18 hours then water was added to quench the reaction. The reaction mixture was partitioned between EtOAc/water and the organic phase dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2) to give 2-benzyloxy-3-cyanopyridine as a pale yellow oil which crystallised on standing (11.4 g, 75%).