Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH3:4][N:5]([CH3:26])[CH2:6][CH2:7][NH:8][S:9]([C:12]1[S:13][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:16]=1)(=[O:11])=[O:10].Br[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:39]=[C:38]([CH:40]3[CH2:42][CH2:41]3)[NH:37][N:36]=2)[C:31]([Br:43])=[CH:30][N:29]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:43][C:31]1[C:32]([NH:34][C:35]2[CH:39]=[C:38]([CH:40]3[CH2:42][CH2:41]3)[NH:37][N:36]=2)=[N:33][C:28]([C:14]2[S:13][C:12]([S:9]([NH:8][CH2:7][CH2:6][N:5]([CH3:4])[CH3:26])(=[O:10])=[O:11])=[CH:16][CH:15]=2)=[N:29][CH:30]=1
Reactant: Brc1ncc(Br)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: CN(C)CCNS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)CCNS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Yield: 20 %

Procedure:
A mixture of Pd(dppf)Cl2.CH2Cl2 (182 mg, 0.22 mmol, 0.1 equiv.), the crude N-(2-(dimethyl amino)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide and 2,5-dibromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (700 mg, 1.95 mmol, 1.0 eq) in dioxane (20 mL) and saturated Na2CO3 aqueous (2 mL) was heated at 100° C. for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, and extracted with THF. The combined organic layers were purified by silica gel chromatography to afford compound 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-(2-(dimethylamino)ethyl)thiophene-2-sulfonamide (200 mg, 20% over 2 steps). LC-MS (m/z)=512.0, 514.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1Cl)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O-:9])=[O:8].Cl.N1CCCCC1>>[N+:7]([C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O-:9])=[O:8]
Reactant: C1CCNCC1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Product: O=C(c1ccccc1)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 0.07 h

Procedure:
15 ml. of piperidine are added at onee to 13 g. of 3-nitro-4-chloro-benzophenone under stirring. Due to the highly exothermic reaction the mixture warms to 98° to 100°C within 4 to 5 minutes, thereafter piperidine hydrochloride starts to separate from the homogeneous reaction mixture. The mixture is stirred for 10 minutes at 98° to 100°C, thereafter cooled, the product is then triturated with 30 ml. of n-hexane, and filtered. The crystalline substance is washed on the filter with 2×30 ml. of n-hexane, subjected to effective suction well, and suspended several times in distilled water to remove piperidine hydrochloride. The obtained product is dried until a constant weight is obtained. 15.5 g. of crystalline 3-nitro-4-piperidino-benzophenone are obtained; m.p.: 77°C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:24]=[C:25]=[O:26])[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:24][C:25](=[O:26])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NCc1ccco1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(NCc1ccco1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with furfurylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (15.3 mg, 28%) having the following characteristics.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[C:3]=1[Br:16]
Reactant: BrBr
Reactant: Nc1ccc2nc[nH]c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc2nc[nH]c2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.08 g of 5-aminobenzimidazole in 20 mL of glacial acetic acid are added 2.68 g of sodium acetate. To this solution is added dropwise 0.4 mL of bromine. The resulting brown precipitate is stirred at room temperature for 2 hours. The reaction mixture is rotary evaporated and the residue is diluted with water and ethyl acetate. The mixture is basified with 1 N sodium hydroxide and decanted. The organic layer is washed with water followed by brine. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 12.5 to 16.5% methanol/methylene chloride followed by recrystallization from hexanes/ethyl acetate to provide 887 mg of 5-amino-4-bromobenzimidazole as a pale brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=[C:9]([NH2:16])[C:8]=2[N:7]=[C:6]1[CH2:17][O:18][CH2:19][CH3:20].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[NH2:16][C:9]1[C:8]2[N:7]=[C:6]([CH2:17][O:18][CH2:19][CH3:20])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:13]=2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)C(C)C
Yield: 59.2 %

Procedure:
Using the method of Example 19, 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.00 g, 3.6 mmol) was reacted with isobutyryl chloride (0.42 mL, 40 mmol) to provide 0.74 g of N-{3-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]propyl}-2-methylpropanamide as an off white solid, m.p. 179.1-179.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8](=[O:21])/[CH:9]=[C:10]2\[S:11][CH:12]=[C:13]([CH3:20])[N:14]\2[CH2:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:32][C:33]([CH3:35])=[O:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8](=[O:21])/[CH:9]=[C:10]2\[S:11][C:12]([C:33]([OH:34])([CH3:35])[CH3:32])=[C:13]([CH3:20])[N:14]\2[CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1C(=O)/C=C1\SC=C(C)N1CC1CCC1
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/C=C1\SC(C(C)(C)O)=C(C)N1CC1CCC1
Temperature: 25 °C

Procedure:
To a solution of Example 169B (140 mg, 4 mmol) in tetrahydrofuran (4 mL) at −78° C. was added lithium diisopropylamide (2 M, 0.6 mL). Acetone (81 μL, 1.2 mmol) was added after 5 min. The reaction was quenched with saturated ammonium chloride (10 mL) after 10 min and the reaction mixture was allowed to warm to room temperature. The reaction was extracted with ethyl acetate (3×10 mL). The organics were combined, washed with brine, dried with sodium sulfate and concentrated. The residue was purified by chromatography over silica gel (dichloromethane-EtOAc 5:1 as eluent) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.48 (s, 6 H) 1.80-1.93 (m, 4 H) 1.99-2.04 (m, 2 H) 2.35 (s, 3 H) 2.68-2.82 (m, 1 H) 3.86 (s, 3 H) 3.96 (d, J=6.78 Hz, 2 H) 5.49 (s, 1 H) 6.53 (s, 1 H) 7.10 (d, J=8.82 Hz, 1 H) 7.39 (dd, J=8.82, 2.71 Hz, 1 H) 7.63 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 408 (M+H)+. Anal calcd for C21H26ClNO3S.0.7H2O: C, 59.97; H, 6.57; N, 3.33. Found: C, 59.76; H, 6.76; N, 3.02.
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.[C:11](OCC)(=[O:13])[CH3:12]>C(OC=C)(=O)C>[C:11]([O:10][CH2:9][C@H:8]1[O:1][CH:2]=[CH:3][C@@H:4]([OH:5])[C@@H:6]1[OH:7])(=[O:13])[CH3:12]
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reactant: CCOC(C)=O
Solvent: C=COC(C)=O
Product: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
1.022 g (7 mmol) of glucal are taken up in 2 ml of ethyl acetate and 30 ml of vinyl acetate, 400 mg of lipase from Candida cylindracea lipase OF (Meito Sangyo Co. Ltd.) are added, and the mixture is stirred at room temperature overnight. After the reusable enzyme has been separated off, and subsequent chromatography or crystallization, 1.12-1.25 g of 6-O-acetylglucal (85-95% yield) are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH2:8]O)=[CH:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[S:3]1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1COCC1>[CH3:1][N:2]1[C:7]([CH2:8][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[S:3]1
Reactant: C1COCCN1
Reactant: CN1Sc2sccc2C=C1CO
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1Sc2sccc2C=C1CN1CCOCC1
Yield: 84 %

Procedure:
To a solution of the product from Step C (0.79 g, 3.42 mmol) and triethylamine (1.04 g, 10.3 mmol) in anhydrous THF (30 mL) at ambient temperature was added methanesulfonic anhydride (0.89 g, 5.13 mmol) with stirring. After 30 min morpholine (2 mL) was added and the mixture stirred for 1 h at ambient temperature and then heated at reflux temperature for 1 h. The volatiles were evaporated and a saturated aqueous solution of sodium bicarbonate (80 mL) was added. This mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts were dried (MgSO4) and evaporated to give a viscous oil which was purified by column chromatography (silica, 30 to 50% ethyl acetate/hexane) to give a white solid (0.82 g, 84%): mp 104°-106° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:23])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:11]([CH3:14])[C:12]=1O.[NH2:24][NH2:25]>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:10]2[C:9](=[O:23])[NH:24][N:25]=[C:12]([CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:11]=2[CH3:14])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C2=C(C)C(O)=C(c3ccccc3F)C2=O)c1
Reactant: NN
Solvent: CCO
Product: COc1cccc(-c2c(C)c(Cc3ccccc3F)n[nH]c2=O)c1

Procedure:
A solution of 2-(2-fluorophenyl)-3-hydroxy-4-methyl-5-(3-methoxyphenyl)-2,4-cyclopentadienone (310 mg, 1 mmol) and hydrazine (0.2 mL) in ethanol (5 mL) was heated at reflux for 30 minutes. The resulting solution was concentrated in vacuo and the residue was dissolved in dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo to give the desired compound as a colorless oil. 1H NMR (CDCl3): 2.14 (s, 3H), 3.27 (d, J=13.8 Hz, 1H), 3.43 (d, J=13.8 Hz, 1H), 6.70-7.25 (m, 8H); MS:325 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[NH2:4].CCN=C=NCCCN(C)C.[C:33](O)(=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:33]([NH:4][C@H:3]([C@H:5]([OH:6])/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][OH:1])(=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO)NC(=O)CCCCCCCCCCCCCCCCC
Yield: 75 %

Procedure:
To a solution of sphingosine (100 mg, 0.33 mmol) in CH2Cl2 (3 mL) was added EDCI (128 mg, 0.66 mmol) and DMAP (cat.). Under stirring, stearic acid (95 mg, 0.33 mmol in 10 mL CH2Cl2) was added dropwise over a period time of 16 h. The reaction was stirred under argon for 24 h at rt. Solvent was evaporated and the residue was applied to silica gel column chromatography (CHCl3:MeOH=9:1, Rf=0.43) to afford 8 as a white powder (140 mg, 75%). 1H NMR (600 MHz, CDCl3) δ 0.88 (t, J=6.8 Hz, 6H), 1.26-1.40 (m, 50H), 1.64 (t, J=7.2 Hz, 2H), 2.06 (dd, J=14.4, 7.2 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H), 3.71 (m, 1H), 3.91-3.97 (m, 2H), 4.32 (m, 1H), 5.42 (dd, J=15.6, 6.6 Hz, 1H), 5.79 (dt, J=15.6, 6.6 Hz, 1H), 6.28 (d, J=7.2 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 14.3, 22.9, 26.0, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 32.2, 32.6, 54.7, 62.8, 74.9, 129.0, 134.6, 174.2. ESIMS calc'd for C36H71NNaO3 [M+Na]+ 588.53. found: 588.18.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16](=[NH:20])OCC)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:21](N)[CH2:22][NH2:23]>C(O)C>[ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16]3[NH:20][CH2:21][CH2:22][N:23]=3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: NCCN
Reactant: CCOC(=N)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2ccc(C3=NCCN3)o2)cc1
Yield: 86.4 %

Procedure:
A mixture of 39 g (0.13 mole) of ethyl 5-(4-nitrophenyl)-2-furimidate hydrochloride and 8.6 g (0.14 mole) of ethylenediamine in 400 ml of absolute ethanol was heated under reflux for 61/2 hr and stood in a refrigerator overnight. The yellow solid was collected by filtration and washed with anhydrous ether to give 33 g (85%) of product, m.p. > 300°.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:2].C(NC(C)C)(C)C.[Li].[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>C1COCC1>[CH3:17][Si:18]([CH3:20])([CH3:19])[C:5]1[S:6][CH:7]=[CH:8][C:4]=1[NH:3][CH:1]=[O:2]
Reactant: O=CNc1ccsc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1sccc1NC=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3- Formylaminothiophene (Bull. Soc. Chim. Fr. 1976,151) (2 g), dissolved in dry THF (20 ml), was dropped into a freshly prepared solution of lithium diisopropylamine (0.035 mol) in THF (35 ml) at −70° C. The solution was warmed to −20° C. and stirred for 30 minutes, then cooled again to −70° C., whereupon trimethylsilylchloride (5 ml) was added. After stirring for an additional hour at this temperature the mixture was slowly warmed to room temperature and stirred for 4 hours. Quenching with a saturated solution of ammonium chloride, extracting with ethyl acetate, drying over sodium sulfate, removing the solvent and applying chromatography on silica gel (hexane:ethyl acetate 2:1) yielded 2-trimethylsilyl-3-formylaminothiophene (1.2 g) (m.p. 74-76° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:36][N+:37]([O-])=O)([C:32]([F:35])([F:34])[F:33])[CH2:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18]2([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[O:17][CH2:16]3)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:34])([F:33])[F:35])[CH2:10][C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18]3([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]3)[O:17][CH2:16]4)=[N:37][CH2:36]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)cc(Cl)c3)C(F)(F)F)ccc12
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc12

Procedure:
The solution of tert-butyl 5′-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-(nitromethyl)butanoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate) (Preparation 11, 1.02 g, 1.74 mmol) in ethanol (12 mL) was purged with nitrogen gas for 30 minutes. To this reaction mixture was added pre washed Raney-Nickel (0.24 g 50% suspension in water). Resulting reaction mixture was stirred under hydrogen atmosphere using balloon for 16 hours at room temperature. After completion of starting material, the reaction mixture was filtered through celite bed and bed was washed with 10% MeOH in DCM (30 mL). Filtrate was concentrated under reduced pressure to get off white solid 1.2 g (crude). Crude compound was purified by column chromatography on silica gel (230-400 mesh). Desired compound was eluted in 10% EtOAc in n-Hexane to get off white semi solid (0.54 g, 57.45%). 1H NMR (400 MHz, CDCl3) δ: 1.53 (s, 9H), 3.45 (d, J=17.2 Hz, 1H), 3.76-3.81 (m, 1H), 4.10-4.14 (m, 2H), 4.32 (d, J=9.88 Hz, 2H), 4.43 (d, J=16.88 Hz, 1H), 4.85-4.90 (m, 1H), 5.13 (s, 2H), 7.25 (m, 2H), 7.36-7.37 (m, 1H), 7.54 (d, J=7.96 Hz, 1H), 7.73 (s, 1H), 7.83 (d, J=7.68 Hz, 1H), LC-MS (m/z): 540.6 (M+H)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 47.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.105 g, 0.217 mmol) obtained in step 2 and methanesulfonamide (0.103 g, 1.09 mmol), the title compound (0.058 g, 47%) was obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][C:3]=1[F:19].[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C@:25]([OH:29])([C:27]#[CH:28])[CH3:26]>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([C:28]#[C:27][C@:25]([C:21]4[S:20][CH:24]=[CH:23][N:22]=4)([OH:29])[CH3:26])[CH:10]=3)[C:6]([CH3:18])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(Br)c(F)cc12
Reactant: C#C[C@@](C)(O)c1nccs1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#C[C@@](C)(O)c3nccs3)c(F)cc12

Procedure:
The title compound was prepared by the procedure described in Example 2-b by reacting 4-(6-bromo-5-fluoro-3-methylindazol-1-yl)pyrimidin-2-amine with (2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol: 1H NMR (500 MHz, DMSO) delta 1.96 (3H, s), 2.55 (3H, s), 7.02 (3H, s), 7.15 (1H, br. s), 7.71 (1H, d, J=3.15 Hz), 7.79 (1H, s), 7.82 (1H, d, J=8.83 Hz), 8.26 (1H, d, J=5.52 Hz), 8.92 (1H, d, J=6.46 Hz); LC-MS m/z=+395.35 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].Cl[CH2:15][C:16]([OH:18])=[O:17]>O>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:15][C:16]([OH:18])=[O:17]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc2ccccc2c1
Temperature: 70 °C
Yield: 14.5 %

Procedure:
To a solution of potassium hydroxide (10.0 g, 0.175 mol) in H2O (100 mL) was added 2-naphthol (10.43 g, 72 mmol), followed by 2-chloroacetic acid (7.79 g, 83 mmol). The resulting mixture was heated at 70° C. for 4 h, then allowed to cool. The mixture was filtered, and the filtrate was extracted with EtOAc. The aqueous phase was made acidic by the addition of 3N HCl and extracted with EtOAc. The organic phase from the acidic extraction was washed successively with H2O and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (2.11 g, 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].S([CH2:24][N+:25]#[C-:26])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([C:8]2[O:9][CH:26]=[N:25][CH:24]=2)[CH:10]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(-c2cnco2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 5-methoxy-2-nitro-benzaldehyde (3.5 g, 19.3 mmol), tosylmethyl-isocyanide (4.5 g, 23.05 mmol) and potassium carbonate (6.7 g, 48.5 mmol) in methanol (40 mL) was stirred at room temperature for 4 h. The resulting red-orange suspension was concentrated and the residue diluted with ethyl acetate. The mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford a yellow oil. This oil was purified via column chromatography on silica gel (gradient elution with 0-10% methanol-methylenechloride) to afford 5-(5-methoxy-2-nitrophenyl)oxazole.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:23])=[C:20](O)[CH:21]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:23])=[C:18]([CH:17]=1)[O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1OC1CCNCC1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1 from tert-butyl 4-hydroxypiperidine-1-carboxylate and 5-bromo-2-chlorophenol.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8](Cl)[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:14]([NH:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH3:15]>>[CH2:1]([O:5][C:6]1[N:11]=[C:10]([N:16]([CH2:14][CH3:15])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:9]=[C:8]([N:16]([CH2:14][CH3:15])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCNc1cccc(O)c1
Reactant: CCCCOc1nc(Cl)nc(Cl)n1
Product: CCCCOc1nc(N(CC)c2cccc(O)c2)nc(N(CC)c2cccc(O)c2)n1
Yield: 47 %

Procedure:
This compound was obtained (yield 47%) based on the method described in Production Example 1B using 6-butoxy-2,4-dichloro-1,3,5-triazine instead of the 2,4-dichloro-6-ethyl-1,3,5-triazine, and using 3-ethylaminophenol instead of the 3-aminophenol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:19]#[N:20])[N:13]=1)(=O)C>CO>[OH:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]#[N:20])[C:15]([CH3:18])=[CH:16][CH:17]=1
Reactant: CC(=O)OCc1ccc(C)c(C#N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(CO)nc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Potassium carbonate (82 mg) was added to a solution of (6-cyano-5-methyl-2-pyridinyl)methyl acetate (3.62 g) in methanol (25 ml) and the mixture stirred under argon at ambient temperature for 2 hours. It was concentrated in vacuo to ca. ¼ volume and water (50 ml) added. The mixture was neutralized with 5% acetic acid (1.5 ml) and extracted with dichloromethane (50 ml then 2×25 ml). The combined extracts were washed with brine (25 ml), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from ether:hexane to afford the title compound (2.26 g, 80%) as a pale buff solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][N:12]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[F:28])[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)C.[Cl-].[NH4+].C(OCC)C>O1CCCC1>[F:28][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:22]=1[N:12]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)CN(c1ccncc1F)n1ccc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCN(c1ccncc1F)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of lithium aluminum hydride (1M solution, 70 ml) cooled to 0° C., was added a solution of N-(3-fluoro-4-pyridinyl)-N-(1H-indol-1-yl)glycine ethyl ester (11.4 g) in 125 ml tetrahydrofuran in thirty minutes. After stirring at 0° C. for one hour, a solution of ammonium chloride was added, followed by 300 ml ethyl ether. The mixture was filtered, and the filtrate evaporated to a solid 10 g; which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined, then evaporated to yield 6.1 g of N-(3-fluoropyridin-4-yl)-N-(1H-indol-1-yl)-2-aminoethanol, as a solid, m.p. 133°-5° C.