Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]2[N:12]([CH:13]=1)[CH2:11][CH2:10][S:9]2(=[O:15])=[O:14])(=O)C.N>>[OH:4][CH2:5][C:6]1[N:7]=[C:8]2[N:12]([CH:13]=1)[CH2:11][CH2:10][S:9]2(=[O:15])=[O:14]
Reactant: CC(=O)OCc1cn2c(n1)S(=O)(=O)CC2
Agent: N
Product: O=S1(=O)CCn2cc(CO)nc21
Reaction time: 2.5 h

Procedure:
6-Acetoxymethyl-2,3-dihydroimidazo[2,1-b]thiazole-1,1-dioxide (305 mg, 1.33 mmol) was treated with methanolic ammonia (prepared by saturating methanol (20 ml) with ammonia gas then diluting with more methanol (20 ml)) at room temperature. After 2.5 h, the volatiles were removed under reduced pressure and the residue triturated with diethyl ether and the resulting solid collected by filtration, washed with diethyl ether and dried in air (207 mg, 83%) (Found: M+ 188.0256. C6H8N2O3S requires M 188.0256); nmax (nujol) 3354, 1377, 1325 and 1133 cm-1 ; dH [250 MHz; (CD3)2SO] 4.14 (2H, t, J 6Hz), 4.40 (2H, d, J 6Hz), 4.54 (2H, t, J 6Hz), 5.20 (1H, t, J 6Hz, exchangeable), 7.36 (1H, s).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=[N+:13]=[N-:14]>>[ClH:1].[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][N:12]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:14]=[N:13]1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccco1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3ccco3)nn2)c[nH]1
Yield: 72.3 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.068 g, 0.399 mmol) was reacted with 2-azidomethyl furan (0.059 g, 0.478 mmol) following the general procedure for click reactions outlined above to produce 4-[2-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidazol-2-ylamine hydrochloride (0.085 g, 72%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.06 (s, 1H), δ 7.53 (s, 1H), δ 6.59 (t, 1H), δ 6.49 (s, 1H), δ 6.44 (dd, 1H), δ 3.05 (t, 2H), δ 2.89 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 156.4, 154.9, 147.5, 144.1, 126.0, 125.1, 123.8, 110.7, 109.3, 69.8, 23.8, 17.4 ppm; HRMS (ESI) calcd for C12H14N6O (M+) 259.1301. found 259.1305.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](OCC)=O.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][C@@H:19]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:35]2[C:34](=[O:40])[CH2:33][C@@:32]2([CH3:41])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[C:29](=[O:31])[CH3:30])[CH2:20]1.[H-].[Na+].Cl>CS(C)=O.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:30][C:29](=[O:31])[C@@H:28]1[C@:32]2([CH3:41])[C@H:25]([C@H:24]3[C@H:35]([C:34](=[O:40])[CH2:33]2)[C@:36]2([CH3:39])[C@H:21]([CH2:20][C@H:19]([O:18][CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][O:12]4)[CH2:38][CH2:37]2)[CH2:22][CH2:23]3)[CH2:26][CH2:27]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CCOC(=O)c1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: C[C@]12CC[C@@H](OC3CCCCO3)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCc4ccccn4)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 0.5 h

Procedure:
Ethyl picolinate (1.0 ml.) was added to a mixture of 3α-(tetrahydropyran-2ξ-yloxy)-5α-pregnane-11,20-dione (840 mg) and sodium hydride (130 mg.) in dry dimethyl sulphoxide (15 ml.). The mixture was stirred, under N2, for 1/2 hr., then treated with methanol and poured into 2N-hydrochloric acid. The precipitate was collected, washed and dried to give 21-picolinyl-3α-(tetrahydropyran-2ξ-yloxy)-5α-pregnane-11,20-dione (695 mg.).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25](O)=[O:26])=[CH:24][C:19]=2[O:18][CH2:17]1.OC1C2N=NNC=2C=CC=1.C(O)C(N)(CO)CO>CN(C)C=O.C(#N)C>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)=[O:26])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2ccc3c(c2)OCO3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 1a) (8 mg, 35 μmol) and benzo[d][1,3]dioxole-5-carboxylic acid (7 mg, 42 μmol) were each dissolved in 200 uL dimethylformamide. Si-Carbodiimide resin (70 mg, 70 μmol) was loaded into a 1.2 mL 96 well Greiner plate, followed by the addition of amine and acid. Hydroxybenzotriazole (6 mg, 42 μmol) was dissolved in 100 uL dimethylformamide and was added into the reaction well. The reaction was shaken overnight at room temperature. To remove excess carboxylic acid and hydroxybenzotriazole, PS-Trisamine resin (35 mg, 70 μmol) was added into the reaction mixture and was allowed to shake overnight at room temperature. 200 uL of Acetonitrile was added into the reaction well and shaken for 1 minute. The top clear solution was transferred into a new plate. The extraction process was repeated two more times. The solution was evaporated under vacuum and gave the desired product. Yield 6%. MS M+H calculated 341.1. Found 341.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]#[N:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]([NH2:19])=[N:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#C[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1

Procedure:
A solution of benzyl-(2S)-2-cyano-4,4-difluoropyrrolidine-1-carboxylate, hydroxylamine hydrochloride (1.4 eq.) and triethylamine (1.7 eq.) in ethanol was refluxed under nitrogen for 5 hours. Mixture was concentrated and residues taken up in ethyl acetate and washed with water and brine. Combined organics were dried over Na2SO4 and evaporated to give title compound as a foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:13])[C:3]=1[O:14][CH3:15].[H][H]>C(O)(C)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:13])[C:3]=1[O:14][CH3:15]
Reactant: COc1c(C)cc(CC=C(C)C)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: COc1c(C)cc(CCC(C)C)cc1C
Yield: 68.8 %

Procedure:
A solution of 2,6-dimethyl-4-(3-methyl-2-butenyl)anisole (10 l g, 0.05 mol) in isopropanol (20 mL), together with 5% palladium on carbon (0.1 g) was hydrogenated in a Parr apparatus until the theoretical amount of hydrogen had been consumed. The catalyst was removed by filtration and the solvent evaporated to give a clear residue which was fractionated to afford 7.1 g of the desired product, bp 102°-105° C. (2 mm). NMR (CDCl3) δ0.9 (6H, d), 1.1-2.0 (3H, m), 2.2 (6H, s), 2.5 (2H, t), 3.7 (3H, s), 6.85 (2H, s). IR (film) 3000, 1225, 1025, 870 cm-1. MS (m/e) 206 (M+), 149, 150, 135, 191.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].I[CH:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH:13]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(OC(C)C)c1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To the solution of 2-hydroxy-4-methoxybenzaldehyde 10 (6.6 mmol, 1 equiv.) and 2-iodopropane (7.23 mmol, 1.1 equiv.) in 7 mL of DMF was added K2CO3 (26.3 mmol, 4 equiv.). The reaction was stirred at 45° C. for 18 h. Next day, added DCM 5 mL, filtered off solid, and washed solid with DCM twice. The filtrate was washed by water. And then organic layer was dried over MgSO4, and concentrated. The remaining residues was purified by Biotage SP1:0-20% EtOAc in hexane over 7 CV, 20% EtOAc in hexane over 5 CV.
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][CH:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][O:6]1)(=O)C.[CH3:19][O:20][C:21]([O:25][Si](C)(C)C)=[C:22]([CH3:24])[CH3:23].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:12]([O:11][CH:8]1[CH2:7][O:6][CH:5]([C:22]([CH3:24])([CH3:23])[C:21]([O:20][CH3:19])=[O:25])[CH2:10][CH2:9]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)OC1CCC(OCc2ccccc2)CO1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)(C)C1CCC(OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To a solution of 5-(benzyloxy)tetrahydro-2H-pyran-2-yl acetate (281 mg, 1.123 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (783 mg, 4.49 mmol) in DCM (5 mL) at −78° C. was added BF3.OEt2 (0.228 mL, 1.796 mmol). The reaction mixture was gradually allowed to warm to rt and stirred at rt for 18 h. The reaction mixture was quenched with sat. NaHCO3 (5 mL) and diluted with DCM (20 mL). The organic layer was separated, washed with water, brine, dried (MgSO4) and concentrated. The crude product was purified by silica gel FCC (10-20% EtOAc in hexanes) to afford methyl 2-(5-(benzyloxy)tetrahydro-2H-pyran-2-yl)-2-methylpropanoate as a colorless oil (253 mg). To a solution of methyl 2-(5-(benzyloxy)tetrahydro-2H-pyran-2-yl)-2-methylpropanoate (250 mg) in MeOH (20 mL) was added 10% Pd—C (59.7 mg) and the reaction mixture was hydrogenated at 40 psi overnight. The suspension was filtered and the filtrate was evaporated to dryness to afford methyl 2-(5-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate as a clear oil (188 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([NH2:29])=[N:13][CH2:14][CH2:15][CH2:16][C@H:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18](O)=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:30][NH:31][O:32][CH3:33].Cl.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C@H:17]([C:18]([N:31]([O:32][CH3:33])[CH3:30])=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:29])[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NC(N)=NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
To a suspension of Boc-Arg(Tos)- OH (2 g, 4.7 mmol) in DMF (20 mL) at 0° C. was added MeNHOMe·HCl (1 g, 10.3 mmol), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol). The solution was stirred at 0° C. for 10 hours. DMF was evaporated by vacuum. The oily residue was dissolved in EtOAc (200 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3, water (20 mL), 1 M HCl (10 mL) and sat. NaCl (2×20 mL). The organic layer was dried over MgSO4, filtered and evaporated to give a suspension. The suspension was filtered, and the solid was washed with cold EtOAc (10 mL) and dried to give Boc-Arg(Tos)-N(Me)OMe, shown above, (1.5 g, 70% yield).
Reaction SMILES: N/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[CH:7]1([NH:10][NH2:11])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(O)C>[CH:7]1([N:10]2[C:4]([NH2:5])=[CH:3][C:2]([CH3:6])=[N:11]2)[CH2:9][CH2:8]1
Reactant: NNC1CC1
Reactant: C/C(N)=C/C#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N)n(C2CC2)n1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
(2Z)-3-amino-2-butenenitrile (903 mg, 11.00 mmol), cyclopropylhydrazine (1194 mg, 11 mmol) and triethylamine (3.07 mL, 22.00 mmol) were suspended in ethanol (100 mL) and heated to 70° C. for 16 hours. The solvent was removed in vacuo. The residue was suspended in 50 mL of saturated NaHCO3 and stirred for 10 minutes. The contents were extracted with DCM, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0% to 100% gradient EtOAc:Hex). The product was collected as 310 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.13 (m, 4 H), 2.13 (s, 3 H), 3.06 (m, J=6.95, 6.95, 3.79, 3.54 Hz, 1 H), 3.76-3.88 (m, 2 H), 5.24 (s, 1 H). LCMS(ES) [M+H]+ 138.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([C:27](=O)[NH2:28])[N:26]=2)[CH:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)[CH:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: NC(=O)c1csc(-c2csc(C(O)(Cn3cncn3)c3ccc(F)cc3F)c2)n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1csc(-c2csc(C(O)(Cn3cncn3)c3ccc(F)cc3F)c2)n1
Yield: 69.6 %

Procedure:
1-(2,4-Difluorophenyl)-1-(4-(4-carbamoylthiazol-2-yl)-thiophen-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol (1.2 g) was dissolved in pyridine (7.1 ml). The solution was cooled on an ice bath, and phosphorus oxychloride (0.29 ml) was added thereto. The resultant mixture was stirred for 30 minutes. After the reaction, the reaction mixture was added with saline and extracted with ethyl acetate. An organic layer was washed once with 6N hydrochloric acid (20 ml) and then each once with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline. After the thus-washed organic layer was dried over magnesium sulfate, the solvent was distilled out, and the residue was purified by chromatography on silica gel. Recrystallization from a solution of dichloromethane in ether was further conducted to obtain a solid (800 mg). Melting point: 172°-173° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[CH3:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:5][C:4]([NH:40][CH3:39])=[O:3])[CH:14]=2)[NH:18][N:17]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(C)c2c1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(C)c2c1

Procedure:
3-(3-Methyl-1H-indazol-5-yl)-N-methyl 3-phenyl-acrylamide CCXX was prepared from 3-(3-methyl-1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [C:1]([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](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:29][C:30]=1[OH:31]>CN(C)C=O>[C:1]([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:31][C:30]4[CH:29]=[CH:28][C:27]([C:32]([F:33])([F:34])[F:35])=[CH:26][C:25]=4[Cl:24])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C(F)(F)F)cc4Cl)ncnc32)CC1

Procedure:
4-[4-(2-Chloro-4-trifluoromethyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-chloro-4-hydroxybenzotrifluoride (available from Oakwood Products, Inc., West Columbia, S.C., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.99-2.08 (m, 4H), 2.98-3.07 (m, 2H), 4.08-4.11 (m, 2H), 5.00-5.05 (m, 1H), 7.78-7.80 (m, 1H), 7.89-7.91 (m, 1H), 8.15 (s, 1H), 8.49 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=498.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:29])=[CH:30][CH:31]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[O:10][C:9]=2[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1oc(-c2ccc(F)cc2F)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(-c2ccc(F)cc2F)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 75.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-({cyclohexyl[5-(2,4-difluorophenyl)-2-methyl-3-furyl]methyl}amino)benzoic acid (511 mg) as well as ethyl 3-(methylamino)propanoate (197 mg) to give the title compound (464 mg, 76%) as an amorphous compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1.C[NH:26][NH2:27]>C1COCC1>[NH:26]([C:2]1[N:7]=[C:6]([N:8]([CH3:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1)[NH2:27]
Reactant: CNN
Reactant: CN(c1ccc(OC(F)(F)F)cc1)c1cc(C(F)(F)F)nc(Cl)n1
Solvent: C1CCOC1
Product: CN(c1ccc(OC(F)(F)F)cc1)c1cc(C(F)(F)F)nc(NN)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.5 %

Procedure:
To a solution of XXVIII (475 mg, 1.28 mmol) in dry THF (3 mL) was added methylhydrazine (273 μL, 5.13 mmol). The resulting solution was stirred at room temperature for 18 hrs, the solvent removed in vacuo and the residue taken up in CH2Cl2. The CH2Cl2 solution was washed with H2O, dried over MgSO4, filtered and CH2Cl2 evaporated in vacuo to afford XIX as a yellow oil (0.43 g, 88%): 1H NMR (DMSO-d6) δ 7.48 (app s, 2H), 7.47 (app s, 2H), 5.84 (s, 1H), 4.86 (bs, 2H), 3.42 (s, 3H), 3.19 (s, 3H); ESIUMS 381 (M+H), 366 (M−CH3).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].[P:9](Cl)([Cl:12])([Cl:11])=[O:10].C(N(CC)CC)C>ClCCl>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCNCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)N(CCCl)CCCl
Temperature: -78 °C
Yield: 87 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (6.3 g, 35 mmol), suspended in 80 mL dichloromethane, was cooled to −78° C. under argon and stirred. A solution of phosphoryl chloride (5.41 g, 35 mmol) in 10 mL dichloromethane, followed by a solution of triethylamine (3.53 g, 70 mmol) in 10 mL dichloromethane, was added slowly by syringe. Stirring was continued while the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was washed with 0.01N hydrochloric acid (3×25 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give N,N-bis(2-chloroethyl)phosphoramidic dichloride as a light orange oil that solidified on standing (7.9 g, 87% yield). A 2.2 g aliquot of the crude N,N-bis(2-chloroethyl)phosphoramidic dichloride was purified by flash chromatography on a 12 g silica cartridge, eluting with a gradient of 100% hexane to 67% hexane/33% ethyl acetate over 10 minutes followed by 67% hexane/33% ethyl acetate for a further 10 minutes, to give 1.5 g pure N,N-bis(2-chloroethyl)phosphoramidic dichloride as a white solid after evaporation of the solvents. MS (ES): m/z=275 [C4H8Cl4NOP+NH4+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([OH:25])[CH:11]=2.[CH2:29](I)[CH3:30].[H-].[Na+].CN(C)C=O>C(OCC)(=O)C>[CH2:29]([O:25][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH2:5][C:4]1[CH:26]=[CH:27][CH:28]=[C:2]([F:1])[CH:3]=1)[C:18]1[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]2=1)[CH3:30]
Reactant: CCI
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(O)ccc3n2Cc2cccc(F)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
Add N-[9-(3-fluoro-benzyl)-6-hydroxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (175 mg, 0.46 mmol), ethyl iodide (72 mg 0.46 mmol), and sodium hydride (60% suspension in mineral oil, 37 mg, 0.92 mmol) to dimethylformamide (1 mL) and stir at room temperature overnight. Dilute the reaction with ethyl acetate, wash with water (2×), dry over sodium sulfate, and concentrate. Recrystallize from ethyl acetate/hexanes to obtain the title compound (107 mg, 57%): MS (ES): m/z (M+1); 1H NMR (CDCl3): δ 7.28 (m, 1H), 7.11 (d, 1H), 6.98 (s, 1H), 6.97 (m, 1H), 6.82 (d, 1H), 6.79 (d, 1H), 6.65 (d, 1H), 5.58 (broad s, 1H, NH), 5.22 (s, 2H), 4.44 (m, 1H), 4.09 (q, 2H), 3.15 (dd, 1H), 2.60-2.81 (m, 3H), 2.33 (m, 1H), 2.15 (m, 2H), 1.45 (t, 1H), 1.18 (m, 6H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][NH:7][C:8]1[C:9](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH3:13])=[O:11].[OH-].[Na+]>ClCCl.O>[Br:1][CH2:2][C:3]([N:7]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH3:6])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CNc1ccccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccccc1N(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.6 %

Procedure:
A solution of bromoacetyl bromide (209 g) in dichloromethane (200 ml) was added dropwise to a cooled (ice bath) solution of methyl N-methylanthranilate (168 g) in dichloromethane (1.41). A solution of sodium hydroxide (59 g) in water (400 ml) was added dropwise and the reaction mixture was stirred at room temperature for 20 h. The organic phase was separated and washed with 1M hydrochloric acid (500 ml), brine (300 ml), saturated sodium hydrogen carbonate solution (400 ml), dried (Na2SO4) then evaporated to afford the required product (255 g). 1H NMR (360 MHz, CDCl3) δ3.23 (3H, s), 3.54 (1H, d, J=11 Hz), 3.60 (1H, d, J=11 Hz), 3.90 (3H, s), 7.40 (1H, d, J=8 Hz), 7.51 (1H, dd, J1 =J2 =8 Hz), 7.65 (1H, dd, J1 =J2 =8 Hz), 8.04 (1H, d, J=8 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]1[C:21]2[N:20]=[CH:19][CH:18]=[N:17][C:16]=2[C:15]([C:22](O)=[O:23])=[CH:14][CH:13]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([CH2:32][N:33]([CH3:39])[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[CH:28][CH:27]=1>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][N:33]([CH2:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:22]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[C:12]([C:3]3[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[F:1])=[CH:13][CH:14]=2)=[O:23])=[N:31][CH:30]=1)[CH3:39]
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3nccnc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2-fluoro-3,5-dimethoxy-phenyl)quinoxaline-5-carboxylic acid (Step 94.1), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2) and stirring the reaction mixture for 18 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 519.2 [M+H]+; tR=3.26 min (System 1); TLC: Rf=0.13 (DCM/MeOH/NH3aq, 94:5:1).