Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC[O:3][C:4]1[C:5]([OH:15])=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=[O:10].[Al+3].[Cl-].[Cl-].[Cl-].ClC(Cl)C.Cl>N1C=CC=CC=1>[OH:15][C:5]1[C:4]([OH:3])=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: O=Cc1cc(OCCl)c(O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=Cc1cc(O)c(O)cc1[N+](=O)[O-]
Temperature: 47 °C
Yield: 68.1 %

Procedure:
To a stirred, cooled (0° C.) dispersion of 1.52 g (0.00658 mol) of 5-chloromethoxy-4-hydroxy-2-nitrobenzaldehyde (10), 1 g AlCl3, and 10 ml dry dichloroethane, 2.4 ml of dry pyridine are added. During addition, the reaction mixture is protected from atmospheric moisture, and the temperature is kept below 35° C. When addition is complete, the temperature is raised to 47° C., and maintained for 18 hours. 6N HCl is added, keeping the temperature at 30°-35° C., until the mixture is acidic to Congo Red indicator paper. The acidic solution is extracted with diethyl ether, and the combined ether extracts are dried over Na2SO4. After filtration, the ether is removed at reduced pressure, giving 0.82 g (68%) of (1): mp 201°-202°° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[C:14]3[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH:26]=O)[CH2:21][CH2:20]2)=[CH:5][CH:4]=1.[CH3:30][CH2:31][CH2:32][NH:33][C@@H:34]1[CH2:39][C:38]2[S:40][C:41]([NH2:43])=[N:42][C:37]=2[CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[C:14]3[N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:33]([CH2:32][CH2:31][CH3:30])[CH:34]3[CH2:35][CH2:36][C:37]4[N:42]=[C:41]([NH2:43])[S:40][C:38]=4[CH2:39]3)[CH2:23][CH2:24]2)=[CH:5][CH:4]=1
Reactant: CCCN[C@H]1CCc2nc(N)sc2C1
Reactant: COc1ccc(COc2cccc3c(N4CCN(CC=O)CC4)ccnc23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCN(CCN1CCN(c2ccnc3c(OCc4ccc(OC)cc4)cccc23)CC1)C1CCc2nc(N)sc2C1
Yield: 74.9 %

Procedure:
Compound 27 (1.0 g, 2.55 mmol) was treated with (−)-pramipexole (599 mg, 2.81 mmol) and NaBH(OAc)3 (973 mg, 4.59 mmol) by following procedure A. The reaction mixture was purified by silica gel column chromatography (EtOAc/MeOH, 9:1) to yield 1.12 g (75%) of compound (−)-28 as yellow solid. The 1H NMR of (−)-28 is similar to compound (±)-28.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:27][C:28](Cl)=[O:29].[OH-].[K+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[O:11][CH2:27][C:28]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: OC(CNCc1ccccc1)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COC(c2ccc(Br)cc2)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
To a solution of 2-benzylamino-1-(4-bromo-phenyl)-ethanol (18.95 g; 62 mmol) and Et3N (9.6 mL; 68 mmol) in CH2Cl2 (500 mL) was added dropwise a solution of chloroacetyl chloride (5.4 mL; 68 mmol) in CH2Cl2 (20 mL), at 0° C. After 1 hour at 0° C. the reaction mixture was quenched with 1M aqueous HCl (200 mL). The layers were separated and the organic layer washed with a 5% aqueous NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in 2-propanol (200 mL) and KOH (4.2 g; 75 mmol) was added. The resulting mixture was stirred at RT for 3 hours and subsequently concentrated in vacuo. The crude product was partitioned between CH2Cl2 and 1M aqueous HCl. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 solution, dried (Na2SO4) and evaporated in vacuo to afford 4-benzyl-6-(4-bromo-phenyl)-morpholin-3-one (22.30 g) which was used as such in the next step.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([CH2:23][CH2:24][CH:25]3OCC[O:26]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:3]1.S(=O)(=O)(O)O>O.C(O)(=O)C>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([CH2:23][CH2:24][CH:25]=[O:26])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc2n1CCC1OCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=CCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Temperature: 60 °C
Yield: 761.4 %

Procedure:
A stirred suspension of the product of Example 69B (0.65 g, 0.15 mmol) in water (3 mL) and glacial acetic acid (12 mL) at ambient temperature was treated dropwise with sulfuric acid (1 mL). The mixture was heated to 60° C. for 1 hour, and then diluted with water. The mixture was filtered and the filter cake was washed with water and dried to produce the title compound (0.455 g, 78%). MS (DCI/NH3) m/z 399 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.72 (m, 2H), 4.59 (t, J=6.62 Hz, 2H), 7.17 (dd, J=7.72, 4.78 Hz, 1H), 7.28 (m, 1H), 7.55 (m, 1H), 7.67 (d, J=7.72 Hz, 1H), 8.39 (dd, J=7.72, 1.84 Hz, 1H), 8.52 (dd, J=4.78, 1.84 Hz, 1H), 9.76 (t, J=2.21 Hz, 1H), 9.76 (t, J=2.21 Hz, 1H).
Reaction SMILES: OC(C1C=CC=CC=1)C([NH:5][CH:6]([CH3:16])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O>Cl>[CH3:16][C@@H:6]([NH2:5])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1
Agent: Cl
Product: C[C@@H](N)CCCc1cccnc1

Procedure:
A solution of 145 g of [R-(R*,R*)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide in 900 mL of 6N HCl was treated with 80 mL of conc. HCl and then was heated at reflux for 2 days. After most of the solvent was removed under reduced pressure, the residue was made decidedly basic with 10N NaOH in an argon atmosphere, and extracted with dichloromethane (1×1.2 L; 2×600 mL). The dried (K2CO3) extracts were evaporated and the crude product was distilled to give 78.5 g of (R)-alpha-methyl-3-pyridinebutanamine, (bp 95° C./0.2 mm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)=[N+]=[N-].[OH2:19]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)[O:19][CH:12]1[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: O
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(OC1C=CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of (3-chloro-4-methanesulfonyl-phenyl)-diazo-acetic acid methyl ester (Example 6; 489 mg, 1.69 mmol) in dichloromethane (10 mL) at 25° C. was treated with 2-cyclohexen-1I-ol (0.42 mL, 4.23 mmol) followed by rhodium (11) acetate dimer (15 mg, 0.034 mmol) and the resulting solution was stirred at 25° C. for 1 h. The reaction mixture was diluted with dichloromethane (10 mL), then was poured into water (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 40S column, 75/25 hexanes/ethyl acetate) provided rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid methyl ester (350 mg, 58% yield) as a colorless oil: EI-HRMS m/e calcd for C16H19ClS O5 (M+) 358.0642, found 358.0640.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[N+](=[CH2:13])=[N-]>CCOCC>[CH3:13][O:9][C:8](=[O:10])[C@H:5]([CH2:6][SH:7])[NH:4][C:1](=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Solvent: CCOCC
Product: COC(=O)[C@H](CS)NC(C)=O
Reaction time: 8 h

Procedure:
N-Acetyl-L-cysteine (5 g, 30.6 mM) was treated with excess diazomethane (generated from N-nitrosomethyl urea) in ether for 6 hr at RT. Unreacted starting material was removed by filtration and the resulting yellow filtrate was allowed to stand overnight. The solvent was removed in vacuo and the residue crystallized from Et2O/Pet. ether to give pure N-acetyl-L-cysteine methyl ester (650 mg); mp 73°-76° C. compared to a literature mp of 81°-82° C. in the Journal of Organic Chemistry, Vol. 35, p. 3542 (1970) and 79°-80° C. in the Canadian Jounral of Chemistry, Vol. 44, p. 2517 (1966).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][S:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:21][C:22]1[N:23]=[C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C)C=O>[F:38][CH:36]([F:37])[O:35][C:32]1[CH:33]=[CH:34][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:17][C:14]3[CH:13]=[CH:12][C:11]([CH2:10][S:8]([CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[O:9])=[CH:16][CH:15]=3)[N:23]=2)=[CH:30][CH:31]=1
Reactant: FC(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(OC(F)F)cc3)n2)cc1
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A solution of 126 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfinylmethyl)-phenol in 4 ml N,N-dimethylformamide was treated at 0° C. with 14 mg (0.55 mmol) sodium hydride and stirred at that temperature for 30 min, then 143 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-difluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued over night at room temperature. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, and purified on silica. Elution with ethyl acetate/methanol (0 to 20%) yielded 123 mg (33%) 1-[2-(4-{2-[2-(E)-(4-difluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl-methanesulfinyl)-ethyl]-1H-[1,2,3]triazole as beige solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=3[Cl:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(C(F)(F)F)ccc3Cl)cccc2c1N
Yield: 42.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-chloro-5-(trifluoromethyl)phenylboronic acid (224 mg, 1.000 mmol) were reacted to afford the title compound (85 mg, 44% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.51 (br, 1H), 7.98 (m, 1H), 7.81-7.63 (m, 5H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=409 (M+H). HPLC 2.46 min.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH2:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH:29][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCc3cc(Cl)cc(Cl)c3)ccc2[N+](=O)[O-])CC1
Yield: 41 %

Procedure:
t-Butyl 4-(5-fluoro-2-nitrophenyl)piperazine-1-carboxylate (1.3 mmol), 3,5-dichlorobenzylamine (1.3 mmol), N,N-diisopropylethylamine (1.3 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 72 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (41%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1H), 7.67 (d, 1H), 7.31 (s, 1H), 7.21 (s, 2H), 6.13 (dd, 1H), 5.70 (d, 1H), 4.42 (d, 2H), 3.54 (m, 4H), 3.38 (m, 4H), 1.49 (s, 9 H). MS (ESI) m/z: Calculated: 481.37; Observed: 482.6 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1Cl)([O-:3])=[O:2].[CH3:18][NH2:19].C(O)C>O>[CH3:18][NH:19][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Two and six-tenths grams (.01 mole) of 2,6-dinitro-4-t-butylchlorobenzene was reacted with 3.1 grams of 40% aqueous solution of methylamine in 50 ml. ethanol. The temperature was slowly increased as follows: 30° C for 1 hour; 40° C for 1 hour; 50° C for 1 hour, then 80° C for 5 hours. When the reaction was complete about 100 ml. H2O was added, precipitating the product. This was filtered, washed with portions of H2O and upon recrystallization from ethanol yielded 2.5 grams of N-methyl-2,6-dinitro-4-t-butylaniline as orange needles melting at 129°-130° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[CH2:19]([OH:22])[CH2:20][CH3:21]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:22][CH2:19][CH2:20][CH3:21])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCO
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Agent: [Na]
Product: CCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium propylate in n-propanol there is obtained propyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and therefrom with hydrochloric acid in alcohol there is obtained the hydrochloride, m.p. 147° C. (with decomposition);
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].[CH:27]#[CH:28].[ClH:29]>>[ClH:29].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:27][CH3:28])([OH:14])[C:10]([CH3:15])([CH3:16])[CH:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC2N(Cc3ccccc3)CCC(=O)C2(C)C)cc1
Reactant: C#C
Agent: Cl
Agent: [Li]
Product: CCC1(O)CCN(Cc2ccccc2)C(Cc2ccc(OC)cc2)C1(C)C
Yield: 55 %

Procedure:
In a manner similar to the method described in example 47, 5 g of 1-benzyl-3,3-dimethyl-2-(p-methoxybenzyl)-4-piperidone is reacted with acetylene lithium (prepared from 1 g of lithium in 75 ml of liquid ammonia). The crude product from this reaction is reduced catalytically as described before, leading to the above-mentioned compound which is secured as the hydrochloride. Yield 55%. Melting point 171° - 172° C with decomposition.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC[C@H](O)CCl
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H](O)CO
Temperature: 70 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
A mixture of 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (150 mg, 395 μmol) and (S)-3-chloro-propane-1,2-diol (366 mg, 3.31 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at 70° C. for 48 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (95 mg) as a pale brown oil; LC-MS**: tR=0.88 min, [M+H]+=454.08; 1H NMR (CDCl3): δ1.34 (t, J=7.0 Hz, 3H), 1.67-1.79 (m, 2H), 1.82-1.96 (m, 4H), 2.04-2.15 (m, 2H), 2.43 (s, 3H), 2.79 (q, J=7.0 Hz, 2H), 3.18-3.29 (m, 1H), 3.81-3.99 (m, 4H), 4.01 (s, 3H), 4.15-4.22 (m, 1H), 7.30 (s, 1H), 7.49 (s, 1H), 7.93 (s, 1H), 7.94 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.C(N(CC)CC)C.[NH2:28][CH2:29][CH2:30][OH:31]>C(Cl)(Cl)Cl>[OH:31][CH2:30][CH2:29][NH:28][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: NCCO
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCO)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
The crude product (130 mg, 0.39 mmol) from the preparation of 2-(5-amino-3-methyl-1H-pyrazol-4-yl)benzothiazole-6-sulfonyl chloride was suspended in chloroform. Triethylamine (0.1 mL) and 2-aminoethanol (26 mg, 0.43 mmol) were then added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the product was purified using preparative TLC eluting with EtOAc:hexanes:MeOH=6/4/0.3 to yield 22 mg (16%) of the product as a cream coloured powder. MS (m/z, ES+): 354 (M+1, 100%); 1H NMR (400 MHz, ppm, DMSO-d6): δ 12.25-11.75 (br s, 1H, exchangeable), 8.47 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.59 (br s, 1H, SO2NH, exchangeable), 7-5.5 (br s, 2H, exchangeable), 4.66 (t, J=5.6 Hz, 1H, OH, exchangeable), 3.34 (m, J=6.2 Hz, 2H), 2.80 (br s, 2H), 2.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][N:25]1[C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:28]3[CH2:27][CH2:26][N:25]([C:30]4[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=4)[CH:24]([CH3:23])[CH2:29]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(-c4ccccc4)n3)CC2C)c1

Procedure:
114 mg (85%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 2-methyl-1-m-tolylpiperazine (49 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][O:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][O:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cncc(OCc2cccc(OCc3ccccc3)c2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(COc2cccc(COc3cncc(N4CCNCC4)n3)c2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from the product obtained in step 1 above (1.62 g, 4.96 mmol), piperazine (1.28 g, 14.9 mmol) and K2CO3 (0.70 g, 5.1 mmol). The yield of the title compound was 1.16 g (62%) and was obtained as an oil. HRMS m/z calcd for C22H24N4O2 (M)+ 376.1899, found 376.1890. Anal. (C22H24N4O2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(Cl)Cl>[CH3:16][NH:17][C:18]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:19]
Reactant: CN=C=O
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Solvent: ClCCl
Product: CNC(=O)Nc1ccc2c(c1)C(=O)NC(=O)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3 g. (14.7 mMole) 7-amino-4,4-dimethylisoquinoline-1,3-dione were dissolved in 100 ml. methylene chloride, mixed with 5 ml. methyl isocyanate, while cooling, and then further stirred for 2 hours at 25° C. Subsequently, the reaction mixture was evaporated, cooled, filtered off with suction and recrystallised from methanol. Yield: 3.7 g. (96.4% of theory); m.p. 257°-258° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([NH2:11])[CH2:5][C@H:6]1[CH2:9][C@H:8]([CH3:10])[CH2:7]1.C(N(CC)C(C)C)(C)C.[Cl:22][C:23]1[CH:56]=[CH:55][CH:54]=[CH:53][C:24]=1[O:25][C:26]1[CH2:30]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:28](=[O:52])[CH:27]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:11]1[CH2:30][C:26]([O:25][C:24]2[CH:53]=[CH:54][CH:55]=[CH:56][C:23]=2[Cl:22])=[CH:27][C:28]1=[O:52])[CH2:5][C@H:6]1[CH2:7][C@H:8]([CH3:10])[CH2:9]1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Reactant: COC(=O)C(N)C[C@H]1C[C@H](C)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C[C@H]1C[C@H](C)C1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 80 °C
Yield: 34.5 %

Procedure:
In a small pressure bottle was placed a mixture of 2-amino-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (147 mg, 0.86 mmol), acetonitrile (6 mL) and N,N-diisopropylethylamine (220 μL, 1.03 mmol) which was heated to 80° C. To this mixture was added (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 61, 276 mg, 0.86 mmol) and the tube sealed and heated at 100° C. overnight. The mixture was cooled to room temperature and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 16% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (108 mg, 35%) as an amber oil: HR-ES-MS m/z calculated for C19H22NO4Cl [M+H]+ 364.1310, observed 364.1310.
Reaction SMILES: FC1C([O:8][C:9]([C:11]2[C:16]([Cl:17])=[N:15][C:14]3=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH:20]=[C:13]3[C:12]=2[NH2:30])=O)=C(F)C(F)=C(F)C=1F.[NH3:35]>C1COCC1>[NH2:30][C:12]1[C:13]2[C:14](=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH:20]=2)[N:15]=[C:16]([Cl:17])[C:11]=1[C:9]([NH2:35])=[O:8]
Reactant: N
Reactant: COc1ccc(Cn2cc3c(N)c(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)c(Cl)nc3n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc3c(N)c(C(N)=O)c(Cl)nc3n2)cc1
Reaction time: 8 h

Procedure:
A solution of 4-amino-6-chloro-2-(4-methoxyphenyl)methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid pentafluorophenyl ester (374 mg) in anhydrous THF was saturated with NH3 gas and stirred overnight. Removal of the solvent gave the desired product as a white solid (contain some pentafluorophenol). LC: 2.60 (Gradient 1); MH+: 332.